Nanomaterials 12 00552 v2

nanomaterials
Review
How the Physicochemical Properties of Manufactured
Nanomaterials Affect Their Performance in Dispersion and
Their Applications in Biomedicine: A Review
Spiros H. Anastasiadis 1,2, * , Kiriaki Chrissopoulou 1 , Emmanuel Stratakis 1,3 , Paraskevi Kavatzikidou 1 ,
Georgia Kaklamani 1 and Anthi Ranella 1
1 Institute of Electronic Structure and Laser, Foundation for Research and Technology-Hellas, N. Plastira 100,
700 13 Heraklion, Crete, Greece; kiki@iesl.forth.gr (K.C.); stratak@iesl.forth.gr (E.S.);
ekavatzi@iesl.forth.gr (P.K.); georgina@iesl.forth.gr (G.K.); ranthi@iesl.forth.gr (A.R.)
2 Department of Chemistry, University of Crete, 700 13 Heraklion, Crete, Greece
3 Department of Physics, University of Crete, 700 13 Heraklion, Crete, Greece
* Correspondence: spiros@iesl.forth.gr; Tel.: +30-2810-391466
Abstract: The growth in novel synthesis methods and in the range of possible applications has led to
the development of a large variety of manufactured nanomaterials (MNMs), which can, in principle,
come into close contact with humans and be dispersed in the environment. The nanomaterials
interact with the surrounding environment, this being either the proteins and/or cells in a biological
medium or the matrix constituent in a dispersion or composite, and an interface is formed whose
properties depend on the physicochemical interactions and on colloidal forces. The development
Citation: Anastasiadis, S.H.; of predictive relationships between the characteristics of individual MNMs and their potential
Chrissopoulou, K.; Stratakis, E.;
practical use critically depends on how the key parameters of MNMs, such as the size, shape,
Kavatzikidou, P.; Kaklamani, G.;
surface chemistry, surface charge, surface coating, etc., affect the behavior in a test medium. This
Ranella, A. How the Physicochemical
relationship between the biophysicochemical properties of the MNMs and their practical use is
Properties of Manufactured
defined as their functionality; understanding this relationship is very important for the safe use of
Nanomaterials Affect Their
Performance in Dispersion and Their
these nanomaterials. In this mini review, we attempt to identify the key parameters of nanomaterials
Applications in Biomedicine: A and establish a relationship between these and the main MNM functionalities, which would play an
Review. Nanomaterials 2022, 12, 552. important role in the safe design of MNMs; thus, reducing the possible health and environmental risks
https://doi.org/10.3390/ early on in the innovation process, when the functionality of a nanomaterial and its toxicity/safety
nano12030552 will be taken into account in an integrated way. This review aims to contribute to a decision tree
strategy for the optimum design of safe nanomaterials, by going beyond the compromise between
Academic Editors: John Vakros and
George Avgouropoulos
functionality and safety.
Received: 17 November 2021 Keywords: physical/chemical characteristics; functionality; nanoparticles; nanomaterials

Accepted: 1 February 2022
Published: 6 February 2022
Publisher’s Note: MDPI stays neutral

with regard to jurisdictional claims in 1. Introduction
published maps and institutional affil- The rapid expansion of nanotechnology and of the related synthesis and analysis tools
iations. has led to a significant increase of the variety of manufactured nanomaterials (MNMs)
and of their range of applications. The term MNMs signifies intentionally manufactured
materials ‘containing particles, in an unbound state or as an aggregate or as an agglomerate
and where, for 50% or more of the particles in the number size distribution, one or more
Copyright: © 2022 by the authors.
external dimensions is in the size range 1–100 nm’. Moreover, fullerene, graphene, and
Licensee MDPI, Basel, Switzerland.
carbon nanotubes with minimum diameters below 1 nm are included as well. The defini-
This article is an open access article
distributed under the terms and
tion of ‘nanomaterial’ was given in 2011 in a European Commission recommendation [1],
conditions of the Creative Commons
where nanomaterials were also categorized as natural, incidental, or manufactured. This
Attribution (CC BY) license (https:// expansion in the application of MNMs has significantly increased the probability of them
creativecommons.org/licenses/by/ coming in contact with humans, the environment, and, in general, the Earth system [2]. It
4.0/). is, therefore, of great importance to identify all probable deleterious effects that MNMs
Nanomaterials 2022, 12, 552. https://doi.org/10.3390/nano12030552 https://www.mdpi.com/journal/nanomaterials

Nanomaterials 2022, 12, 552 2 of 47
may have on both human health and the environment, early on in the innovation process.
A first step towards achieving this objective is to be able to link the physicochemical charac-
teristics of the manufactured nanomaterials to their functionality. At the same time, much
research work is still required to both, advance our knowledge on the physicochemical
characterization of MNMs, and to explore on how these characteristics and the resulting
properties affect their potential to induce toxicity in different receptors, as well as deter-
mine their ultimate fate [3]. The importance of lacking the right correlations regarding how
physicochemical characteristics influence the fate of manufactured nanomaterials has been
emphasized in reports on the life-cycle assessment of these MNMs [4]. Moreover, correlat-
ing the physico-chemical characteristics of MNMs and their extensive (eco)toxicological
assessment would allow the application of grouping and read-across methodological ap-
proaches, which have been extensively used for chemicals in general and, based on the
similarity between substances and their behavior, could be used to fill data gaps for other
MNMs, without performing additional effort, and time, consuming testing [5]. One should
also refer here to a classic book by Otterstedt and Brandreth [6], which deals with the
chemical and physical principles of methods for the preparation of MNMs, as well as with
the description of their surface and of the methods of its modification. The applications
of small particle technology are also demonstrated, considering how to make technically
important materials.
When any type of a nanomaterial interacts with a biological medium, which can consist
of proteins, membranes, cells, organelles, and nucleic acids, various kinds of nanoparti-
cle/biological interfaces are established, where the behavior is governed by the relevant
biophysicochemical interactions, as well as by colloidal forces. These kinds of interactions
can lead to the formation of protein coronas on the surface of the nanomaterials, wrapping
of nanoparticles by membranes, intracellular uptake, and biocatalytic processes that could
potentially have biocompatible or bio-antagonistic outcomes. At the same time, the nano-
material surface may suffer phase transformations, restructuring, and/or dissolution, due
to the presence of the biomolecules and the dispersing liquid medium. Being able to under-
stand the structure and the behavior at such interfaces would allow predictive relationships
between structure and activity to be developed, which will be governed by the nanomaterial
characteristics, such as size, shape, roughness, surface chemistry, and surface coatings. Such
knowledge will be imperative for the safe use of the nanomaterials [7].
Our main objective has been to identify, classify, and prioritize the physicochemical
characteristics of nanomaterials in relationship to their functionalities, in order to demon-
strate the interrelationship between these different functionalities and to illustrate the effect
of the physicochemical properties on the MNM performance. The number of different
nanoparticles, their properties, and their practical uses are vast, as are their different physic-
ochemical properties and the resulting biophysicochemical interactions at the respective
interfaces. Thus, it is not possible to discuss all of them in sufficient detail. In this work, we
present a short review of how specific key parameters of manufactured nanomaterials affect
some of these functionalities, except toxicity, which is, by itself, a huge field of research. Key
parameters relative to geometry (particle size, particle shape, and aspect ratio), chemistry
(composition, surface groups, surface charge), crystallinity, morphology (topology, rough-
ness, porosity, and surface area), surface functionalization (surface coatings, reactivity, and
stability), and test media (mostly aqueous) are discussed in relation to MNM functionalities.
These functionalities are discussed in terms of two groups: performance or properties, on
the one hand, and applications, on the other. In the properties/performance functionalities
we have included dispersion ability in aqueous media, solubility/dissolution characteris-
tics, and hydrophobicity/hydrophilicity, which are directly affected by the physicochemical
characteristics of the prepared nanomaterials, but, at the same time, they can have an effect
on the activity and the practical uses of the MNMs. In the second functionality group,
we have included applications such as the cellular uptake of the MNMs, as well as their
optical, electronic, magnetic, and catalytic properties. Since the number of MNMs is vast,
we tried to focus our report mainly on certain MNMs that are more frequently encountered
in contact with humans, such as titania (TiO2 ), silica (SiO2 ), zinc oxide (ZnO), cerium oxide
(CeO2 ), iron oxide (Fe3 O4 ), barium sulfate (BaSO4 ), cadmium selenide (CdSe) quantum
dots, gold (Au), silver (Ag), and various carbon nanomaterials such as carbon nanotubes
(CNTs), graphene, graphene oxide, and reduced graphene oxide. It is noted that carbon
black (nano)materials, which are broadly used in tires, are not discussed in this mini review,
mostly because this is a very broad area, where various grades of carbon black are used,
often with a non-disclosed primary particle size distribution, as well as different sizes and
structures of aggregates [8].
One should note that being able to understand such interrelationships will allow
engineering the MNMs so that one can maximize the benefits for functionality, while
reducing the risks to human health and/or the environment and, moreover, being able to
achieve this at an early phase of the innovation process. This would enable the consideration
of safety aspects for humans and the environment early on in the process of designing a
new product, so as to minimize or, even, eliminate the risks of adverse effects during its life
cycle, which includes synthesis, storage, use, maintenance, and decommission.
2. How the Key Parameters Affect Functionalities with Respect to Performance

2.1. Dispersion Ability
The state of dispersion of nanomaterials in the different dispersing media is a very
important characteristic of nanoparticulates; yet this state is very challenging to quantify,
since dispersion is a very complicated (and little understood) process [9,10]. Controlling
the dispersion of fine particles and preventing the formation of uncontrollable aggregates
can lead to materials with improved properties [11]. The aggregation of nanomaterials
depends both on the particle characteristics (e.g., size, shape, concentration, surface charge,
and surface roughness) and on the physicochemical properties of the media (e.g., ionic
strength, pH, and/or presence of organic macromolecules) [12]. In the absence of a surface
coating, the aggregation/disaggregation of nanomaterials is mainly controlled by the
intrinsic properties of the particles, such as size and zeta (ζ)-potential, as well as by the
ionic strength of the solutions, as described by the DLVO theory proposed by Derjaguin,
Landau, Verwey, and Overbeek [13,14].
Nanoparticles tend to agglomerate immediately in cell culture media. Thus, the effects
of the various biological dispersion media on the state of aggregation of the nanoparticles
has been extensively investigated in the literature, especially since these are critical in eval-
uating and interpreting the toxicological assay results [15]. At the same time, when natural
organic matter (NOM) is present, it usually increases the stability of the nanoparticles in
water [12,16], whereas chemical surfactants, serum, and/or proteins are frequently used to
improve the dispersion and stabilization of nanoparticles [17].
2.1.1. Dispersibility of Metal and Metal Oxide Nanomaterials

Titanium oxide (TiO2 ) nanoparticles are widely utilized in many different applications,
for example, in cosmetics and sunscreen products; nevertheless, they may be toxic in certain
cases and/or certain environments or aggregate in different culture media and, thus, the
investigation of the degree of their dispersion is critical. Ultrapure water was found to disperse
TiO2 better than freshwater microalgae and daphnia aquatic culture media (Figure 1). The
hydrodynamic size of the nanoparticles was found to slightly depend on concentration in the
former case; whereas, the effect was significantly larger for the latter [18].
In contrast, attempts to disperse TiO2 nanoparticles in water, even under strong
sonication, led to sizes bigger than the hydrodynamic radius of the primary nanoparticles,
indicating that the TiO2 sample consists of a certain number of strong aggregates that cannot
be broken down easily, even when ultra-sonication is utilized [19]; the dispersion state was
much poorer when different cell culture media were used in the absence of any dispersing
agents. Bovine serum albumin (BSA) greatly improved the dispersion of nanoparticles
in many culture media, with the observed differences attributed to the different protein–
nanoparticle interactions in the media. On the other hand, fetal bovine serum (FBS) was
found to be the best agent for dispersing and stabilizing TiO2 nanoparticles, due to the
various proteins it comprises, which function in a synergistic manner. When rat and
mouse bronchoalveolar lavage fluid (BALF) was used as a suspension medium, it was
found to considerably reduce the aggregation of TiO2 (as well as ultrafine and fine carbon
black); whereas, the use of phosphate buffered saline (PBS) containing protein or DPPC
alone, in similar concentrations to those found in BALF, was not successful in satisfactorily
dispersing the particles [20]. In another study, similar nanoparticle size distributions were
Nanomaterials 2022, 12, 552 measured in water without and with bovine serum; whereby, further dilution in Roswell 4 of 51
Park Memorial Institute (RPMI) cell culture medium resulted in significant aggregation [21].
Figure1.1.Dynamic
Figure Dynamiclight
lightscattering
scattering(DLS)
(DLS)results
resultsfor
forthe
thesize
sizeofofTiO
TiO 2 agglomerates as a function of
2 agglomerates as a function of
TiO 2 concentration in water, in freshwater microalgae cultured in Blue-Green medium (BG-11), and
TiO2 concentration in water, in freshwater microalgae cultured in Blue-Green medium (BG-11), and
in daphnia magna cultured in simplified Elendt M7 medium (SM7). * denotes statistical differences
in daphnia magna cultured in simplified Elendt M7 medium (SM7). * denotes statistical differences
from the control [18].
from the control [18].
In contrast,
The attemptsmedium
type of biological to dispersein theTiO 2 nanoparticles in water, even under strong
presence of serum, together with the size of the
sonication, led to sizes bigger than the hydrodynamic
nanoparticles, were found to affect the aggregation behavior radius of ofthe
SiOprimary nanoparticles,
2 nanoparticles; their
indicating
primary sizethat
wasthe TiO2 sample
measured whenconsists
dispersed of aincertain
water or number
mediaofwithout
strong serum
aggregates
[15]. that
In
cannot be broken down easily, even when ultra-sonication is
contrast to SiO2 nanoparticles, which showed a significant dependence of their measured utilized [19]; the dispersion
state
size onwasthe much poorer
dispersion when different
medium and/or on cell
theculture
presence media
of a were
protein, used
theinsize
theofabsence of any
poly(acrylic
dispersing agents. Bovine serum albumin (BSA) greatly improved
acid)-coated cobalt ferrite nanoparticles was found to be insensitive to the medium [22]. the dispersion of
nanoparticles
Moreover, in many
the size cultureiron
of magnetic media,
oxidewith the observedcan
nanoaggregates differences
be kept low,attributed
due to to the
their
different protein–nanoparticle
stabilization via adsorption of FBS interactions
proteinsin thewhereas
[23], media. On thethe other
same hand,reduces
protein fetal bovine
the
serum (FBS) of
agglomeration was zincfound
oxideto be the best[24],
nanoparticles agent for dispersing
similarly to its effect and
on the stabilizing
dispersionTiO of 2
nanoparticles, due to the various proteins it comprises, which
TiO2 nanoparticles mentioned above [19]. For hydroxyapatite nanomaterials, the nanopar- function in a synergistic
manner.
ticle When ratwith
size decreased andincreasing
mouse bronchoalveolar
FBS concentration lavage fluid (BALF)
in conjunction was used
with stirring, as a
which
suspension
provides the medium,
necessaryitsteric
was andfound to considerably
electrostatic reduce
repulsion the aggregation
to overcome of TiO2van
the attractive (as der
well
as ultrafine
Waals fine carbon
forces and preserve theblack);
dispersionwhereas, the for
stability useaof phosphate
long buffered
period [25]. Fetal saline (PBS)
calf serum
containing
(FCS) was not protein or DPPC
successful alone, in similar
in supplementing theconcentrations
dispersion of Au to nanoparticles
those found inofBALF, was
different
not successful
sizes in deionized in water
satisfactorily dispersing
(DI); whereas, whenthe particles
it was used in [20]. In another
Dulbecco’s study, eagle’s
modified similar
nanoparticle
medium size distributions
(DMEM), were measured
it led to the formation in water
of complexes without and with bovine serum;
[26].
whereby, further stable
Temporarily dilution in Roswell
small aggregatesParkwere
Memorialformed Institute
when (RPMI) cell culture medium
Al2 O3 nanoparticles were
dispersed
resulted in either in deionized
significant water (DI)
aggregation [21].or in ethylene glycol [27], whereas CeO2 nanopar-
ticles formed
The typea of more stable medium
biological dispersion in only in water,ofinserum,
the presence comparison
together to with
a fishthe
medium in
size of the
which sedimentation
nanoparticles, were foundwas clearly observed
to affect [28]. However,
the aggregation behavior in ofboth
SiOcases dispersionstheir
2 nanoparticles; of
small aggregates
primary size wasand not of primary
measured particles were
when dispersed obtained.
in water or media Moreover,
withoutcitrate
serumcapped
[15]. In
silver (Ag) nanoparticles in aqueous matrices were found to aggregate
contrast to SiO2 nanoparticles, which showed a significant dependence of their measured more pronouncedly
insize
salty
on sea water compared
the dispersion medium to and/or
lake fresh water,
on the due to
presence ofthe presence
a protein, theof natural
size organic
of poly(acrylic
matter (NOM),
acid)-coated i.e., alginate
cobalt humic and fulvic
ferrite nanoparticles was foundacids,toandbe the low ionic
insensitive to strength
the mediumof fresh
[22].
Moreover, the size of magnetic iron oxide nanoaggregates can be kept low, due to their
stabilization via adsorption of FBS proteins [23], whereas the same protein reduces the
agglomeration of zinc oxide nanoparticles [24], similarly to its effect on the dispersion of
TiO2 nanoparticles mentioned above [19]. For hydroxyapatite nanomaterials, the
water when compared to sea water [29]. The measured hydrodynamic radii were also
found to decrease with increasing pH.
The dispersion of Ag nanoparticles, their aggregation, as well as the size of these ag-
gregates and their stability were found to be very different in different organic solvents [30].
Ag (80 nm), hydrocarbon-coated Ag (15 nm and 25 nm), and polysaccharide-coated Ag
(10, 25–30 and 80 nm) showed a similar tendency since they agglomerate at almost the
same size when they are dispersed in water or media with serum; when media without
serum were utilized, higher agglomeration sizes were obtained [31]. At the same time, the
dispersion of metal and metal oxide nanoparticles, such as Al, Al2 O3 , Cu, SiO2 , TiO2 , and
Ag, was investigated in water, cell culture media (RPMI-1640) only, and/or cell culture
media with serum [31]. In the majority of cases, media without serum exhibited the worst
dispersing ability, irrespectively of the kind of nanoparticles, their size, and/or their coat-
ing; whereas, in general, the media with serum were the best, differences in the final sizes
were observed depending on the kind of nanoparticles in water. Moreover, the effect of the
particle primary size on the agglomeration was very weak, if not absent. TiO2 nanoparticles
exhibited high agglomeration, whereas SiO2 particles and SiO2 -coated fluorophores (35, 51,
and 110 nm) were the only nanoparticles that were dispersed in a way whereby the size of
the primary particles could be measured. The dispersibility of CuO and ZnO nanoparticles
was tested in different mineral and complex test environments, as well as its relationship
with toxicity towards selected environmentally relevant test organisms and mammalian
cells in vitro [32]. Both, CuO and ZnO nanoparticles were very unstable and sedimentation
was observed. A considerably high degree of agglomeration/sedimentation was observed
in the mineral media that are used for key regulatory ecotoxicological assays (crustaceans,
algae). On the contrary, the components of the complex test media (test environment
with organic components) were found to be critical in dispersing the nanoparticles and
preventing their sedimentation.
The crystallinity and the primary size of nanoparticles are also factors that influence
their dispersibility. In the case of TiO2 , 100% anatase, 61–39% rutile-to-anatase, 40–60%
rutile-to-anatase, as well as completely amorphous TiO2 nanoparticles were evaluated in
water and in media with and without serum [31]. The amorphous TiO2 showed a high
degree of agglomeration in all three suspending media, whereas the other TiO2 particles
showed slightly smaller aggregates in water, and only the 61% rutile TiO2 showed a
significant decrease in media with serum. The 61% rutile titania also exhibited the highest
values of zeta-potential. Moreover, when the size of the TiO2 nanoparticles was studied
utilizing nominally 5, 10, 16, 50, and 100 nm nanoparticles, a high agglomeration was
obtained in all three media, except the 10 nm TiO2 in water. The effect of nanoparticle
size on dispersibility has also been investigated with Au nanoparticles of 10, 50, 100, and
250 nm in aqueous suspensions diluted in phosphate buffered saline (PBS), to obtain a
physiological solution [33]. The coexistence of agglomerates consisting of loosely arranged
nanoparticles with individual ones was observed in all dispersions, except for the one of
the largest nanoparticles, where there was not any obvious clustering. Particle shape also
influences the electrostatic and steric repulsive forces, which are much stronger between
two plate-like particles than between two spherical particles of the same volume, due to
the much larger interaction surface between the plate-like particles [34].
2.1.2. Dispersibility of Carbon Nanomaterials

More so than the dispersion of inorganic, metallic, or metal oxide nanoparticles, the
prevention of aggregation in carbon nanomaterials is of utmost importance, since their
agglomeration may hinder the realization of their excellent properties. Enhanced dispersion
and stabilization of carbon nanomaterials (CNMs), such as graphene oxide, graphene,
carbon nanotubes, and fullerenes, especially in water, is a critical challenge, because of their
tendency to aggregate, particularly in aqueous systems, due to significant van der Waals
attractions and their specific hydrophobic interactions [35]. It is both the physicochemical
properties of the carbon nanomaterials and the properties of the dispersion medium that
prevention of aggregation in carbon nanomaterials is of utmost importance, since their
agglomeration may hinder the realization of their excellent properties. Enhanced
dispersion and stabilization of carbon nanomaterials (CNMs), such as graphene oxide,
graphene, carbon nanotubes, and fullerenes, especially in water, is a critical challenge,
because of their tendency to aggregate, particularly in aqueous systems, due to significant
van der Waals attractions and their specific hydrophobic interactions [35]. It is both the
physicochemical properties of the carbon nanomaterials and the properties of the
dispersion medium that influence the dispersion stability, which is further enhanced in
influence
aqueous the dispersion
media stability,
with NOM, due which
to theis further enhanced
enhanced in aqueous
interactions media
assisted bywith
the NOM,
CNMs
due to the enhanced
hydrophobic interactions
surfaces. assisted
Both single- andbymulti-wall
the CNMs hydrophobic surfaces.
carbon nanotubes Both single-
(SWCNTs and
and multi-wall carbon nanotubes (SWCNTs and MWCNTs) were
MWCNTs) were found to disperse better in media with NOM than in natural water found to disperse better
in media2);
(Figure with NOM thanfunctionalization
nevertheless, in natural water of (Figure 2); nevertheless,
the MWCNTs functionalization
can improve the dispersionof
the MWCNTs can improve the dispersion and lead to differences among
and lead to differences among the different media [16]. The presence of proteins, lipids, the different
media [16]. The presence
or protein/lipid componentsof proteins,
is cruciallipids, or dispersion
for the protein/lipid components
of carbon is crucial such
nanomaterials for the as
dispersion
fullerenes of carbon
and nanomaterials
single- and multi-wall suchcarbon
as fullerenes and in
nanotubes single- andmedia
various multi-wall carbon
as well [36],
nanotubes in variouslacking
whereas vehicles media aslipids
well [36], whereas vehicles
or proteins lead tolacking lipids or proteins
the formation of the lead to
largest
the formation
agglomerates. of the largest agglomerates.
Figure2.2. Different
Figure Different dispersibilities
dispersibilities among
amongCNT
CNTtypes
typesand
andbetween
betweendifferent
differentmedia,
media,illustrated by
illustrated
CNT dispersions in MHRW-NOM (top) and natural water (bottom). From the left: SWCNT,
by CNT dispersions in MHRW-NOM (top) and natural water (bottom). From the left: SWCNT,
MWCNT-15, MWCNT-30, MWCNT-OH, and MWCNT-COOH. (Reprinted with permission from
MWCNT-15, MWCNT-30, MWCNT-OH, and MWCNT-COOH. (Reprinted with permission from
ref. [16]. Copyright 2018 Elsevier).
ref. [16]. Copyright 2018 Elsevier).
Aqueous suspensions of nanosilver, nanocopper, and fullerenes (C60) [37] were
Aqueous suspensions of nanosilver, nanocopper, and fullerenes (C60) [37] were pre-
prepared in deionized water and in filtered natural river water to examine the effect of
pared in deionized water and in filtered natural river water to examine the effect of different
different concentrations of dissolved organic carbon (DOC) and different ionic strengths
concentrations of dissolved organic carbon (DOC) and different ionic strengths of the so-
of the solutions; it was found that water chemistry influences both the
lutions; it was found that water chemistry influences both the suspension/solubility of
suspension/solubility
the nanomaterials, as wellof theasnanomaterials, as well
their particle size as their particle
distributions. The size distributions.
dispersion The
of carbon
dispersion of carbon nanotubes and carbon black was studied in water,
nanotubes and carbon black was studied in water, in cell culture media (RPMI-1640), in cell culture
media (RPMI-1640),
and/or in cell cultureand/or
mediain incell
theculture media
presence in the[31].
of serum presence of serum
SWCNTs, [31]. SWCNTs,
MWCNT-COOHs,
and CNTs formed aggregates in deionized water, whereas carbon black showed acarbon
MWCNT-COOHs, and CNTs formed aggregates in deionized water, whereas large
black of
range showed a large range
agglomeration sizesof(the
agglomeration
smaller foundsizes
in (the smaller
water) found on
depending in water) depending
the solvent used.
Stable aqueous dispersions of fullerenes, C60 and C70, were prepared in a different study
by injecting a saturated suspension of fullerenes in tetrahydofuran (THF) into water and
subsequently removing the THF by purging with nitrogen gas [38]. Fullerenes were dis-
persed as monodisperse clusters in water, and the obtained dispersions exhibited excellent
colloidal stability, despite the absence of any stabilizing agent. This was attributed to the
negatively charged surfaces that led to significant electrostatic repulsion and, thus, caused
the stability of the dispersions.
2.1.3. Surface Modification and Dispersibility

One of the most widely used methods to improve the dispersion stability of nanopar-
ticles is their surface modification [39]. This necessitates a different designing of the surface
structure, depending on the type of nanoparticle, as well as of the dispersing liquid media.
Colloidal stability can be achieved by the adsorption, grafting, and/or coating of polymers,
surfactants, and charged or biological molecules [34,40,41] that will provide electrostatic
or steric repulsion between nanoparticles, thus, avoiding their agglomeration. In certain
media, in order for a good dispersion of nanoparticles to be achieved, either a formulation
with dispersants (usually amphiphilic molecules) or surface modification is requisite. For
the latter case, the best functioning grafting molecules depend strongly on the size of the
nanoparticle, with surfactants working better for small nanoparticles (<10–50 nm), whereas
alkoxysilanes work better for larger ones (>50 nm) [42].
One of the simplest surface modification methods for improving dispersion stabil-
ity is the adsorption of a polymeric dispersant on the surface of the nanoparticles; this
methodology was presented in a comprehensive review [39]. Cationic or anionic polymer
dispersants are commonly utilized to disperse nanoparticles, in either aqueous media or in
organic solvents with high polarity; the polymer chains generate the steric repulsive force
and increase the surface charge. Poly(acrylic acid) (PAA), sodium salts of PAA, as well
as copolymers of acrylic acid and maleic acid are common anionic polymeric surfactants
utilized to disperse oxide nanoparticles, such as TiO2 , BaTiO3 , Fe2 O3 , MgO, and Al2 O3 ,
whereas polyethyleneimine, PEI, is a commonly used cationic surfactant. The adsorption of
the surfactants on the nanoparticles and the resulting range and magnitude of the repulsive
force are influenced by a combination of various parameters, such as the suspension pH
and solid fraction, the molecular weight of the polymer and its degree of dissociation, as
well as the nanoparticle surface charge and its particle size. It was found that polymeric
surfactants with a high molecular weight diffuse more difficultly around small nanopar-
ticles and, thus, they cannot efficiently adsorb on their surface, failing to improve the
dispersion stability of the suspension. Moreover, the dispersion stability can be affected
by the surfactant structure. For example, for a polymer dispersant with a hydrophilic
and a hydrophobic group, the ratio of the hydrophilic and hydrophobic sites controls the
loop-train structure of the polymer adsorbed onto the particle surface, thus, affecting the
dispersant ability. Copolymers possessing hydrophilic and hydrophobic segments are
often utilized as anionic surfactants, to assist the dispersion of hydrophobic nanoparticles,
such as SiC, CNTs, and coal, in aqueous media, since they can adsorb on the surface via
their hydrophobic segments. Moreover, an aromatic monomer, such as styrene, can further
improve the adsorption via both hydrophobic and π-π interactions. At the same time,
the hydrophilic parts provide the necessary compatibility with the aqueous dispersing
media and create an effective repulsive steric force. Cationic polymers, such as PEI, can
also be utilized to enhance the dispersion of hydrophobic particles, such as SiC and CNTs,
in aqueous media. Another method to improve the degree of dispersion of nanoparticles
in various liquids is chemical modification of their surface. Silane coupling agents are
utilized to alter the surfaces of oxide nanoparticles via the introduction of various reactive
groups, such as epoxides, amines, and vinyls, on the particle surface and the subsequent
grafting-from or grafting-to of polymers onto the surface. It is noted that neutral polymers,
such as poly(ethylene oxide) or dextran, can also be employed as stealth coating agents to
improve the colloidal stability and pass through physiological barriers; the most common
cell targeting agents are proteins, enzymes, antibodies, or nucleotides [43].
Adsorption of certain surfactants on the outer or the inner surface of halloysite nan-
otubes has been utilized to increase their dispersibility, either in water or in organic solvents.
At the same time, covalent or non-covalent functionalization of boron nitride nanotubes
creates homogeneous dispersions in aqueous and organic media [44]. The dispersion
stability of copper oxide (CuO) was investigated in different media, in their pristine form
and when modified by four different stabilizing agents that gave them a negative (sodium
ascorbate, ASC, and sodium citrate, CIT), a positive (polyethylenimine, PEI), or a neutral
(polyvinylpyrrolidone, PVP) surface charge. The results showed that, in media with low
ionic strength, the first two materials improved the dispersion by improving the repulsive
potential, due to the negative charge, where PEI had the most significant effect, since
it provides both electrostatic and steric stabilization, due to the positive charge and its
polymeric nature, respectively. Amino acid and protein-rich media, however, control the
stability irrespectively of the coating molecule [45].
An optimal concentration of sodium dodecylbenzene sulfonate (SDBS) was attained
in the case of CuO and Al2 O3 particles in deionized water, based on the reduction of their
hydrodynamic radii that led to a concurrent decrease of viscosity and increase of thermal
conductivity [46]. At the same time, SDBS and cetyltrimethylammonium bromide (CTAB)
were utilized at low concentration and at exactly the critical micelle concentration (CMC)
to assist the Al2 O3 nanoparticle dispersion [47]. SDBS at CMC showed the best dispersion,
because of the positive surface charge of alumina in the aqueous medium and its strong
affinity for anionic groups, in contrast to CTAB, which, being a cationic surfactant, is
repelled by the positively charged alumina surfaces. Similarly, SDBS was found to provide
a better stability of Al2 O3 nanoparticles than CTAB or SDS, whose performance was rather
poor. In the former case, the measured hydrodynamic radius of the nanoparticles was
approximately that of the primary ones, taking into account the size of the additional
surfactant layer [48]. Beyond the stabilization in a simple nanofluid, SDBS shows a better
and longer stabilization, lower hydrodynamic size, and narrower polydispersity than SDS,
even for nanohybrid TiO2 -Ag nanoparticles [49]. In a similar way, a certain concentration of
PVP surfactants in a Al2 O3 /ethylene glycol nanofluid provides the most stable dispersions
for long durations, due to the polymeric chain interactions, in contrast to the case when
SDS is used, where a fast sedimentation is observed [50].
In the case of titanium dioxide/distilled water nanofluids, the more stable dispersions
were obtained when PVP was utilized as a stabilizer, whereas the use of the non-ionic
surfactant polyoxyethylenesorbitan monolaurate (Tween 20) led to systems with lower
viscosity; heat transfer is improved by both additives [51]. SDS also significantly influences
the stability of TiO2 nanoparticles, via different processes, which include surface adsorption
and agglomeration (Figure 3).
These processes are reversible (desorption, disagglomeration) when the pH or the
SDS concentration changes, whereas the concentration of the surfactants, the presence of
divalent electrolytes, and the mixing procedure (successive or punctual addition) are of
significant importance, because of the complex interplay among the adsorption/desorption
of the surfactant, specific adsorption, hydrophobic effects, charge cation bridging, inversion,
agglomeration, and disagglomeration [52].
The anionic surfactant SDS was found to be the best among non-ionic (TritonX 100,
PEG), anionic (SDS), and cationic surfactants (CTAB) in stabilizing ZnO in aqueous media,
as its utilization resulted in particles with a smaller size distribution and longer resistance
to sedimentation, especially following sonication [53]. In contrast, the non-ionic surfactant
PVP resulted in smaller hydrodynamic radii of zirgonium oxide, ZrO2 , compared to the
ionic SDBS and to CTAB. PVP was found to create stable aqueous dispersions over a
long period of time, with its concentration not playing a significant role [54]. Different
concentrations of TiO2 were better dispersed when FBS was used as the surfactant in the
conventional F-12K plus FBS cell culture medium, in comparison with cases where the
non-ionic block copolymer pluronic F68 or the semi-synthetic plant-derived DPPC were
used as anti-agglomerating agents [17]. In all cases, the size of the particles increased as
a function of their concentration. Similar results were observed when nickel oxide (NiO)
nanoparticles were investigated in the same media. Covalently bound dextran on the
surface of permanently magnetic nanoplatelets ensured robust steric stabilization in differ-
ent physiological buffers and in complex biological media. These kinds of nanoparticles
are keen to agglomerate, not only because of the van der Waals attraction, but due to
dipole–dipole interactions as well [34]. The presence of humic acid (HA) as the natural
organic matter in conjunction with ultra-sonication (and, more specifically, the addition of
the dispersant before the sonication) were critical for achieving a stable dispersion of TiO2
nanoparticles, together with the concentration of HA and the pH. At the same time, the
optimum
Nanomaterials 2022, 12, 552 values of these parameters depend on the anatase or rutile crystalline phases of 9 o
the nanoparticles [55].
Figure 3. (Left) Schematic representations of TiO2 and SDS interactions and agglomerate formati
Figure 3. (Left) Schematic representations of TiO2 and SDS interactions and agglomerate formation.
(a): TiO2–SDS agglomerates at pH 3.1. Hydrophobic interactions promote the formation of la
(a): TiO2 –SDS agglomerates.
agglomerates (b): at pH 3.1. Hydrophobic interactions promote the formation of large
TiO2 agglomerate formation at pH 8.2 in the presence of divalent cations (
agglomerates. Cation
(b): TiObridging
2 agglomerate
betweenformation at pH 8.2agglomeration.
TiO2 promotes in the presence(c): of divalent
TiO2–SDScations (⊕).
agglomeration in
Cation bridging between TiO
presence of divalent
2 promotes agglomeration. (c): TiO
cations at pH 8.2. Cation bridging –SDS agglomeration in the pres-
2 between SDS tails destabilizes the complex
ence of divalent(Right)
cationsZ-average diameters
at pH 8.2. and ζ-potential
Cation bridging between as aSDS
function of pH for (a):
tails destabilizes the[SDS] = 40 mg L−1: cha
complexes.
neutralization and inversion is observed. SDS–TiO complex properties
(Right) Z-average diameters and ζ-potential as a function of pH for (a): [SDS] = 40 mg L : charge
2 are − 1
mainly controlled by
TiO 2 surface properties. (b): [SDS] = 200 mg L−1: the impact of SDS properties on the behavior of
neutralization and inversion is observed. SDS–TiO2 complex properties are mainly controlled by
TiO2–SDS complexes is more pronounced. Charge neutralization occurs and the isoelectric poin
the TiO2 surface properties. (b): [SDS] = 200 mg L−1 : the impact of SDS properties on the behavior
obtained at pH 5.2; by further increasing the pH, negative values are obtained, due to surf
of the TiO2 –SDS complexes is more pronounced. Charge neutralization occurs and the isoelectric
deprotonation. (c): [SDS] = 1442 mg L−1: the SDS–TiO2 complexes exhibit stable Z-average diame
point is obtained
andatζ-potential
pH 5.2; by in
further increasing
the full pH range.the[TiO
pH,2]negative
= 50 mg Lvalues are obtained,
−1 (Reprinted due
from ref. to surface
[52]. Copyright 2017 T
deprotonation.Royal
(c): [SDS] = 1442
Society mg L−1 : the SDS–TiO2 complexes exhibit stable Z-average diameter
of Chemistry).
and ζ-potential in the full pH range. [TiO2 ] = 50 mg L−1 (Reprinted from ref. [52]. Copyright 2017
The Royal Society ofThe anionic surfactant SDS was found to be the best among non-ionic (TritonX 1
Chemistry).
PEG), anionic (SDS), and cationic surfactants (CTAB) in stabilizing ZnO in aqueous med
Magneticasiron oxide nanoparticles
its utilization were also
resulted in particles functionalized
with a smaller size by the acidicand
distribution form of resistan
longer
sophorolipidsto[56]. No stable dispersions were achieved in the absence of sophorolipids,
sedimentation, especially following sonication [53]. In contrast, the non-ionic surfact
whereas when sophorolipids
PVP were employed,
resulted in smaller a stableradii
hydrodynamic colloidal suspension
of zirgonium of maghemite
oxide, ZrO2, compared to
Fe2 O3 nanoparticles, in coexistence with a black/brown precipitate, was obtained;
ionic SDBS and to CTAB. PVP was found to create stable aqueous dispersions the pres- over a lo
ence of the precipitate was attributed to the nanoparticle aggregation before
period of time, with its concentration not playing a significant role [54].the addition of Differ
the sophorolipids and/or the insufficient complexation by the sophorolipids. An increase
concentrations of TiO2 were better dispersed when FBS was used as the surfactant in
in temperature further assisted
conventional F-12K theplus
dispersion.
FBS cellDifferent organic ligands
culture medium, have been
in comparison utilized
with cases where
to influence the colloidal stability of TiO nanoparticles as a function of pH,
non-ionic block copolymer pluronic F68 or the semi-synthetic plant-derived
2 electrolyte con-DPPC w
centration, and dispersing medium, where different behaviors were observed depending
used as anti-agglomerating agents [17]. In all cases, the size of the particles increased a
on their functional group
function (Figure
of their 4). It was shown
concentration. Similarthat, in certain
results were cases, the when
observed behavior wasoxide (N
nickel
more influenced by the electrolyte concentration than by the pH, in contrast to
nanoparticles were investigated in the same media. Covalently bound dextran on other cases
surface of permanently magnetic nanoplatelets ensured robust steric stabilization
different physiological buffers and in complex biological media. These kinds
nanoparticles are keen to agglomerate, not only because of the van der Waals attracti
but due to dipole–dipole interactions as well [34]. The presence of humic acid (HA) as
where, not only was the pH the main parameter, but it showed opposite effects for different
Nanomaterials 2022, 12, 552 modifiers. There were cases where none of these parameters were found to significantly
11 of 51
influence the behavior or the final hydrodynamic radii measured in the dispersions [57].
Figure 4. Zeta potential (Z-pot), hydrodynamic diameter (dz-ave), and sedimentation velocity (sed V)
Figure 4. Zeta potential (Z-pot), hydrodynamic diameter (dz-ave ), and sedimentation velocity (sed
of pristine and functionalized Aeroxide® P25 TiO2 nanoparticles (declared average particle size: 21
V)nm)
of pristine and functionalized Aeroxide ® P25 TiO nanoparticles (declared average particle size:
dispersed in 1 and 10 mM NaCl solution for pH 2 values from 2 to 10. Catechol (CAT), 3,4-
21dihydroxybenzaldehyde
nm) dispersed in 1 and(CHO),
10 mM3,4-dihydroxybenzoic
NaCl solution for pH acidvalues fromdopaminehydrochloride
(COOH), 2 to 10. Catechol (CAT),
(DOP), salicylic acid (SAL),(CHO),
3,4-dihydroxybenzaldehyde and polyethylene glycol (PEG,
3,4-dihydroxybenzoic Mv(COOH),
acid 100,000) dopaminehydrochloride
were utilized for the
functionalization.
(DOP), salicylic acid(Reprinted
(SAL), andwith permissionglycol
polyethylene from ref. [57].MCopyright
(PEG, 2018 Elsevier).
v 100,000) were utilized for the function-
alization. (Reprinted with permission from ref. [57]. Copyright 2018 Elsevier).
Surfactants also improve the stability of carbon nanomaterials (CNMs) in water,
because of their adsorption via hydrophobic and π–π interactions. Ionic surfactants lead
Various mineral and complex test environments were used to examine the dispersibility
of Ag nanoparticles [32]. In all liquid media, coated silver nanoparticles were significantly
more stable compared to the uncoated ones. This was in agreement with the results of an inde-
pendent study [58], which showed that uncoated Ag nanoparticles tend to precipitate in high
ionic strength suspensions and sediment within a few hours. Furthermore, the dispersibility
of both bare and surface-coated Ag nanoparticles with either poly(vinyl pyrrolidone) (PVP)
or oleic acid (OA) was investigated, as well as its relation to bioaccumulation and reproduc-
tive toxicity in earthworms versus that of Ag ions [59]. Nanoparticles coated with PVP are
hydrophilic and they usually form stable suspensions in polar solvents [60], whereas ones
coated with OA are amphiphilic and form stable suspensions in both polar and non-polar
solvents, as well as in polar/non-polar interface layers, depending on the pH of the suspen-
sion [61,62]. The primary particle diameters were determined by TEM, which showed that the
OA-coated particles had a slightly smaller mean diameter than the PVP-coated ones. Dynamic
light scattering measurements in DI water were in agreement with TEM concerning the size
distributions of the PVP-coated nanoparticles, whereas they showed a greater ratio of larger
aggregates for the OA-coated ones.
Surfactants also improve the stability of carbon nanomaterials (CNMs) in water, be-
cause of their adsorption via hydrophobic and π–π interactions. Ionic surfactants lead to
stabilization of CNMs dispersions via the electrostatic repulsion between the charged hy-
drophilic head groups; a similar dispersion ability is obtained for both anionic and cationic
types. Additionally, the purification process, as well as the surface-functionalization that
defines the nanomaterial surface charge, influence the mechanism by which ionic surfac-
tants can adsorb on the CNM surface. The phase behavior of carbon nanotubes (CNTs) in
suspension depends strongly on the kind of surfactant used, its concentration, and on the
type of interaction. Understanding the adsorption mechanism of ionic surfactants and the
prediction of the colloidal stability of CNTs in different media requires knowledge of their
surface charge. CNTs can be dispersed in water when coated by surfactants adsorbed on
their surfaces, preferentially with those that have a relatively high hydrophilic–lipophilic
balance [63]. The stability of aqueous dispersions of CNTs usually increases when sodium
dodecyl sulfate (SDS) is utilized [64]. UV–vis spectroscopy has shown that the CNT/SDS
dispersions exhibit very high stability; the amount of nanotubes in the supernatant liquid
above the sediment decreased by only 15%, whereas the corresponding decrease in the case
of bare CNTs was ~50% after 500 h was allowed for sedimentation. The interaction between
CNTs and SDS via the hydrophobic segment results in a higher negative surface charge
and steric repulsion, which enhances the stability of the CNT/SDS dispersion. It was,
thus, concluded that a surfactant comprising of a single, long, straight-chain hydrophobic
segment and a terminal hydrophilic group can be a suitable dispersant for stable CNT
dispersions. Moreover, Tween 80 (T80), which is a non-ionic surfactant, was found to
enhance the dispersion of multi-walled CNTs in aqueous media, whereas the presence of
biological media, such as RPMI and DMEM cell culture media, improved the dispersion
even further [65]. In that case, the stabilization was ascribed to steric effects, as there was
no change in the zeta potential measurements.
2.1.4. Dispersion Medium and Dispersibility

The effect of ionic strength (IS) and solution pH on nanoparticle dispersion has also
been extensively studied, for example for anatase TiO2 nanoparticles with a primary particle
size of 15 nm; the authors studied their influence on the hydrodynamic size and on the
surface charge of the resulting ‘particles’ [66]. In one case, the nanoparticles were dispersed
in NaCl solution with different concentrations to investigate the effect of the IS at constant
pH and, in another, in solutions with the same ionic strength, but different pH adjusted
by using HCl, NaOH and NaCl, and their combination. A large increase in the average
size was found with increasing solution IS, since, at low IS, the electrostatic repulsive
forces are dominant, whereas, when IS increases, the attractive forces dominate, resulting
in a highly-agglomerated dispersion. Measurements of the average diameter of the TiO2
dispersions and of the zeta potential as a function of pH at constant ionic strength were
also performed. For pH values far from the isoelectric point (IEP), a high value of zeta
potential was measured, and the electrostatic repulsion prevailed over the van der Waals
attraction and agglomeration was suppressed. For pH approaching the IEP, the low surface
charge leads to a reduction of the repulsive forces, which results in an increase of the
hydrodynamic size and in the formation of large flocs that sediment due to gravitational
forces in a short time. Analogous conclusions were obtained when the aggregation of TiO2
was investigated for different concentrations of Suwannee river fulvic acid (SRFA) and
various values of pH and ionic strengths [67]. The aggregation of bare TiO2 nanoparticles
increased for pHs close to the zero point of charge, whereas at constant pH, aggregation
increased with ionic strength. Furthermore, adsorption of SRFA resulted in a smaller degree
of aggregation of the TiO2 nanoparticles, presumably due to enhanced steric repulsion.
Dynamic light scattering showed that the TiO2 particles readily form stable aggregates
at pH ~4.5 in a NaCl solution adjusted to an ionic strength of 0.0045 M [68]. At the same
pH, when the ionic strength increased to 0.0165 M, micron-sized aggregates were formed
within 15 min. At all other pH values, micron-sized aggregates were found to form faster
than the minimum detection time of 5 min, even at low ionic strengths when NaCl was
used. However, micron-sized aggregates form much faster in an aqueous suspension in the
presence of CaCl2 than in respective suspensions in NaCl, showing that divalent cations
may enhance the aggregation of titania.
Similar observations were made when the agglomeration of SiO2 nanoparticles in
aqueous media was studied for different ionic strengths and pH values [69]. Addition of
different salts (NaCl, MgCl2 , BaCl2 and CaCl2 ) caused aggregation of the SiO2 nanoparticles,
whereas a change of the pH within the range investigated did not influence the degree
of aggregation in the absence of an electrolyte. The type of cation significantly affected
the aggregation, with divalent cations (Mg2+ , Ba2+ and Ca2+ ) being more efficient in
destabilizing the nanoparticle suspension than the monovalent Na+ cations.
The effect of natural organic matter (NOM) on the aggregation of anatase TiO2 nanopar-
ticles was also evaluated [70]. Changes in the particle size were measured as a function
of the concentration of three different electrolytes (NaCl, Na2 SO4 , and CaCl2 ) and of the
suspension pH. In general, the influence of the addition of an electrolyte in the absence of
NOM followed DLVO theory. When the level of NOM adsorption on the titania surface
was low, aggregation was induced, whereas an increase of the surface coverage could
reduce the particle aggregation, even at high ionic strengths. The surface coverage was
determined by the ratio of the concentration of NOM to that of the nanoparticles, whereas
the mixing procedure was proven to be important, since it led to different final aggrega-
tion states. Ionic strength strongly influenced the aggregation behavior, whereas divalent
cations and anions led to stronger destabilization of negatively or positively charged titania
particles, respectively. Nanoparticles that were positively charged at low pH were more
easily destabilized by SO4 2− compared to Cl− , whereas the opposite was observed for Ca2+
compared to Na+ for negatively charged nanoparticles at high pH. The addition of NOM at
concentrations that create stable dispersions increased the stability of the suspensions with
respect to Na2 SO4 and NaCl but did not have much influence when CaCl2 was used.
The effect of concentration of sodium dodecylbenzene sulfonate (SDBS) surfactant
and of pH on the size of ‘nanoparticles’ of alumina (Al2 O3 ) and copper in water was
investigated [71]. Optimal values of SDBS concentration (0.10% for alumina and 0.07% for
copper) and pH (pH ~8.0 for alumina and pH ~9.5 for copper) were found, at which the
effective particle diameters exhibited minimum values. Hexadecyl trimethyl ammonium
bromide assisted in obtaining Cu nanoparticles with more than one order of magnitude
smaller sizes in aqueous suspensions [72].
The degree of aggregation of CNMs increases at low pH, mainly due to the relatively
smaller negative charge, although the degree of dispersion generally depends on the
dispersing agent [35]. The dispersion of CNMs is significantly influenced by the presence
of dissolved ions in water as well, where the aggregation of CNMs increases as the ionic
strength increases, as expected. However, beyond a certain value of the ionic strength,
there is no additional increase in the degree of aggregation, signifying that the electrostatic
repulsive forces are already shielded. Moreover, increasing temperature results in an
increase of the stability of CNM suspensions, most probably because of the disruption of
weak interaction forces, increased Brownian motion (and, thus, collisions), and reduced
zeta potential. Cellulose nanocrystals suspended in water also show pH-dependent size
and viscosity; both quantities increase in acidic or alkaline conditions, whereas they obtain
their lowest values at neutral pH [73].
Synthesized core-shell ZnS-coated CdSe nanocrystal quantum dots (QDs) were further
coated to possess single -NH2 , -COOH, -OH, or dual -NH2 /OH and -OH/COOH functional
groups [74]. The surface charge, as measured by zeta-potential measurements, varied
depending on the functional group; it was found that QD-COOH and QD-OH/COOH
were highly negatively charged, whereas QD-NH2 and QD-NH2 /OH were positively
charged. QD with hydroxyl groups were less negatively charged than the QDs with
carboxylic acid groups, whereas QDs with both -OH and -COOH or -NH2 groups had
median charge. QD-NH2 showed a broad particle distribution in contrast to QDs with
-COOH groups that exhibited a much narrower distribution, while functionalization of the
QD surface with -OH groups led to improved dispersion and stability under hypertonic
conditions. In contrast, all QDs were stable in nonelectrolyte solutions. Moreover, all
functionalized QDs were stable under weak alkaline conditions, whereas only QD-NH2
was stable under acidic conditions.
In conclusion, the investigation of the dispersibility of nanoparticles is a complicated
process, since nanomaterials constitute dynamic entities that undergo physical and chemical
transformations when mixed with environmental, synthetic, or biological media of different
complexities, the characteristics of which affect the behavior to a large extend.
2.2. Solubility and Dissolution of Nanoparticles

The possibility of nanoparticles dissolving within the suspending medium is a key
property that influences their toxicity and, consequently, their biological response, because
it defines the fate of nanoparticles in the human body, as well as in the surrounding
environment [75–78]. The solubility/dissolution of nanomaterials is frequently confused
with their dispersion ability. Dissolution is defined as the dynamic process during which
a particle dissolves in the matrix medium, in order to form a homogeneous solution
or mixture [79]; this occurs when the constituent atoms or molecules have a specific
solubility in the local environment. During this process, molecules from the surface of the
dissolving nanomaterial are transferred to the solution forming a diffusion layer, which
is the volume between the bulk solution and the solid nanomaterial surface that involves
solvated molecules. The nanoparticle dissolution depends on the size [80,81] and the
surface area [82,83], the surface morphology [77], the surface energy [84], the possible
adsorbed species and the state of aggregation of the nanoparticles [85], as well as on the
properties of the diffusion layer and the possible solute concentration in the suspending
medium [79]. Furthermore, the dissolution kinetics depend on the size and, thus, the
surface area as well, explaining why the dissolution of nanoparticles is faster and more
extended in comparison with macroscopic particles of the same material [86,87].
Nanoparticle antibacterial properties [88], toxicity [89], biomedical characteristics, and
environmental impact [90] are strongly associated with their dissolution, since highly-toxic
ions such as Zn2+ , Cu2+ , Cd2+ , Ag+ , etc. may be delivered to the solution [91–94]. It is possi-
ble, however, that a complex suspension—involving partially dissolved nanoparticles, free
ions dissolved from the nanoparticles, and adsorbed ions on the nanoparticle surface—may
be produced through the dissolution process in the surrounding media [95,96]. Figure 5
schematically illustrates that the metal oxide nanomaterial toxicity may originate from [88]
the nanoparticles themselves, the released ions, or the combination of both, while adsorp-
tion of metal ions on the nanoparticles also affects toxicity. Moreover, since the nanoparticle
and environmental impact [90] are strongly associated with their dissolution, since highly-
toxic ions such as Zn2+, Cu2+, Cd2+, Ag+, etc. may be delivered to the solution [91–94]. It is
possible, however, that a complex suspension—involving partially dissolved
nanoparticles, free ions dissolved from the nanoparticles, and adsorbed ions on the
Nanomaterials 2022, 12, 552
nanoparticle surface—may be produced through the dissolution process 14 in ofthe
47
surrounding media [95,96]. Figure 5 schematically illustrates that the metal oxide
nanomaterial toxicity may originate from [88] the nanoparticles themselves, the released
ions, or the combination of both, while adsorption of metal ions on the nanoparticles also
surface
affects interacts directly with
toxicity. Moreover, biological
since systems, surface
the nanoparticle surface interacts
area is a key parameter
directly of their
with biological
biological effect [97].
systems, surface area is a key parameter of their biological effect [97].
Figure5.5.Nanoparticle
Figure Nanoparticletoxicity
toxicitycan
canbe
beattributed
attributedtotothe
thenanoparticles
nanoparticlesthemselves,
themselves,totoreleased
releasedions
ions
from the nanoparticles, or the combination of both. The procedures of dissolution and adsorption
from the nanoparticles, or the combination of both. The procedures of dissolution and adsorption are
both considered to contribute to the nanoparticle toxicity (Reprinted with permission from ref. [88].
Copyright 2016 Elsevier).
Generally, the dissolution of nanoparticles increases as the particle size decreases [98–101].
ZnO nanoparticles, however, do not exhibit major differences in their dissolution characteristics
when compared to particles of micron size [102]; both nanoparticles and microparticles showed
an 80% dissolution when added in Osterhout’s medium. It has also been reported in the
literature that decreasing the particle size can reduce the extent of, or even prohibit, dissolution;
when the dissolution of hydroxyapatite nanoparticles was studied as a function of particle
size, it was observed that it was the larger particles that were prone to dissolution [103]. The
dissolution of silver (Ag) nanoparticles, which affects their antibacterial properties, depends
on their size. The smaller the Ag nanoparticles, the higher the dissolution rate, provided
that aggregation of the nanoparticles is avoided, since this may lead to sedimentation. The
formation of a passivation layer (e.g., an oxide layer) can inhibit their dissolution and, thus,
their antibacterial activity [104]. The effects of the concentration and size of nanomaterials
on the release of silver ions from citrate-capped Ag nanoparticles in a common hydroponic
nutrient medium (quarter-strength Hoagland medium) was investigated, and the kinetics
of ion release was accounted for by a kinetic model within hard sphere collision theory
using the Arrhenius equation; thus, providing insight into the mechanisms of the ion release
kinetics from the Ag nanoparticles [105]. Moreover, when the dissolution in water of PVP-
stabilized and citrate-stabilized Ag nanoparticles was investigated [106], it was observed
that the concentration of released silver ions was limited, whereas the dissolution rate and
degree depended on the functionalization of the particles and on storage temperature. The
dissolution is not only affected by the nanoparticle size, but by their shape and surface
morphology as well [107]; when different shapes of CuO nanoparticles (spherical and rod
shaped) were investigated, it was found that spherical nanoparticles dissolved faster and
to a greater extent compared to rod shaped particles. The kinetics of dissolution due to
oxidative etching of Pt nanoparticles of cubic and icosahedral shapes in aqueous solutions
was investigated using a mixture of HAuCl4 and KCl as oxidative agent. Figure 6 shows the
morphological changes of the icosahedral and the cubic Pt nanoparticles over a period of one
hour. The shape of the nanoparticles was dramatically changed as dissolution proceeded. The
corners became round and, after 1 h, the cube dissolved completely, while a small part of the
icosahedron remained [108].
aterials 2022, 12, 552 16
Figure 6. Morphological changes of icosahedral and cubic Pt Nanoparticles due to dissolution in the
Figure presence
6. Morphological changes of icosahedral and cubic Pt Nanoparticles due to dissolution i
of aqueous solutions with a mixture of HAuCl4 and KCl. (Reprinted with permission from
presence of aqueous solutions with aChemical
ref. [108]. Copyright 2017 American mixtureSociety).
of HAuCl4 and KCl. (Reprinted with permission
ref. [108]. Copyright 2017 American Chemical Society).
Nanoparticle dissolution is also affected by the parameters of the surrounding media,
including pH, water hardness, ionic strength, temperature, and the presence of detergents
Nanoparticle dissolution is also affected by the parameters of the surrounding me
or organic compounds [7,109]. For example, complete dissolution of CuO nanoparticles
including
was pH, water
observed hardness,
in the presence ionic strength,
of media enrichedtemperature,
in amino acids and [110],the presence
whereas of deterg
cysteine
or organic compounds
was found to increase [7,109]. For example,
the Ag nanoparticle complete
dissolution dissolution
[111]. The solubilityof ofCuO nanopart
copper-
based nanoparticles was enhanced at low pH [112], whereas
was observed in the presence of media enriched in amino acids [110], whereas cyst it was observed that ZnS
nanoparticles showed the highest solubility at lower pH (in the range 9–10) and for the
was found
smallesttoparticle
increase size the
[113].Ag nanoparticle
Moreover, at pH 7 (indissolution
DMEM), ZnO [111]. The solubility
nanoparticles dissolved of cop
based significantly
nanoparticles morewas after enhanced at low
48 and 72 h when pH [112],
compared whereasatitpH
to suspensions was observed
4 (in Milli-Q that
water). When
nanoparticles showedthe ZnO thenanoparticle accumulation
highest solubility atinside
lower A-431
pHcells (in was
theinvestigated,
range 9–10) theand fo
authors presented arguments that the toxicity could be attributed to the nanometric size
smallest particle size [113]. Moreover, at pH 7 (in DMEM), ZnO nanoparticles disso
until 24 h of exposure, whereas, after 24 h (up to the 72 h of exposure was studied), both
significantly
releasedmore
Zn2+ ions after
and48 and 72 hplayed
nanoparticles whenancompared
important role to insuspensions at pH 4 (in Mi
the toxicity [83].
water). When the ZnO nanoparticle
The dissolution of nanoparticlesaccumulation
is strongly related inside A-431
with their cells was degree
bioavailability, investigated
of uptake, and toxicity [114]. The toxicity of nanoparticles
authors presented arguments that the toxicity could be attributed to the nanometricis related to their chemical
characteristics and surface chemistry [115,116]; this is due to the possibility of releasing
until 24 h of exposure, whereas, after 24 h (up to the 72 h of exposure was studied),
toxic ions and/or the production of reactive oxygen species (ROS) [117]. Toxic effects
released Zn+2 ions
through and nanoparticles
the production played
of ROS are very likelyanto important role in theoftoxicity
occur for nanoparticles small size [83].
The
and,dissolution
thus, of large of nanoparticles
reactive is strongly
area. Nevertheless, when the related withoftheir
dissolution bioavailability,
nanoparticles takes de
place during the cell culture, it is difficult to identify the origin of the toxic effects. The
of uptake, and toxicity [114]. The toxicity of nanoparticles is related to their chem
toxicity of a number of particles was tested in relation to their dissolution. The authors
characteristics
categorized and surface chemistry
the nanoparticles [115,116];
into soluble (Ca3 (PO4 )this is due to the possibility of relea
2 , Fe2 O3 , ZnO) and insoluble (CeO2 ,
toxic ions
TiO2 , and/or
ZrO2 ), and the production
studied of reactive
the cytotoxicity oxygen
on two different species
cells (ROS)
lines; it was found[117]. Toxic ef
that, for
through the production of ROS are very likely to occur for nanoparticles of small size
thus, of large reactive area. Nevertheless, when the dissolution of nanoparticles t
place during the cell culture, it is difficult to identify the origin of the toxic effects.
toxicity of a number of particles was tested in relation to their dissolution. The aut
high dissolution, the toxic effects were considerably higher compared to those for little or
no dissolution [118].
The solubility of ZnO nanoparticles, with an emphasis on the toxicological effects of
zinc ions, has been widely studied [119]. It has been reported that the higher the nanoparti-
cle dose, the more the cell nuclei are condensed, leading to cell apoptosis [120]. ROS, such as
hydrogen peroxide, superoxide anions, hydroxyl radicals, and organic hydroperoxides, can
be produced in an aqueous suspension of ZnO nanoparticles; these ROS can cause injury
to cells, whereas they also display a strong antibacterial activity [100]. Cytotoxicity studies
of ZnO, CeO2 , and TiO2 nanomaterials and their relation to dissolution suggested that the
toxicity induced by ZnO nanoparticles is due to the dissolution of the ZnO nanoparticles in
the aqueous environment and the release of Zn+ in the culture medium, which is associated
with high levels of ROS. On the other hand, CeO2 showed a cytoprotective behavior by sup-
pressing ROS production; this led to cellular resistance to the oxidative stress. Finally, TiO2
was considered inert, since it did not result in toxic effects on mammalian cells [121]. To
evaluate the toxicity in marine diatoms, ZnO nanoparticle dissolution has been examined in
seawater; the toxicity was attributed to the ZnO dissolution that released zinc cations [122].
Even inert nanoparticles can induce ROS under living conditions; this is due to their ability
to target mitochondria. A number of cellular events can be influenced by ROS, such as sig-
nal transduction, proliferation rate, gene expression, and protein redox regulation. At high
ROS levels, cells may be damaged by altering proteins, deoxidizing lipids, or disrupting
DNA, which can even lead to cancer due to gene transcription modulation [120,123]. The
dissolution of ZnO nanoparticles, their uptake, and the routes they follow to enter LoVo
cells has also been investigated. It was found that ZnO nanoparticles can enter LoVo cells by
passive diffusion, endocytosis, or both, according to their agglomeration state. When ZnO
nanoparticles contact the acidic pH of the lysosomes inside the cells, zinc ions are released.
These ions together with the presence of ZnO nanoparticles produce ROS that cause DNA
damages. Thus, the ZnO nanoparticle toxicity is attributed to a combination of the presence
of the particles and of the zinc ions [124]. ZnO nanoparticle dissolution has been studied in
various biologically relevant solutions, including HEPES, MOPS, and PIPES, where it was
discovered that the buffers affect the dissolution kinetics and toxicity of the nanoparticles.
Experiments on cell viability have shown that the use of buffers decreases the viability of
Jurkat leukemic cells after the introduction of ZnO nanoparticles [125].
The dissolution of silver nanoparticles starts immediately upon exposure to the par-
ticular medium and continues for several hours. The oxidative dissolution of Ag is also
responsible for the toxicity of the nanoparticles, which is ion- and particle-related [77]. The
oxygen present induces the formation of Ag2 O on the surface of the silver nanoparticles
and the release of silver cations in the aqueous solution. Moreover, low pH and smaller
particle size enhance the Ag nanoparticle dissolution [126]. In general, different forms of
silver may be contained within a suspension of Ag nanoparticles, such as free or complexed
Ag+ and Ag+ adsorbed on the nanoparticles. The state of Ag nanoparticles in pure water or
an aqueous nitric acid environment was investigated for a range of pHs, between 0.5 and
6.5 [127]; the findings suggest that the dissolution of silver nanoparticles depends on the
particle size, since larger particles did not dissolve in nitric acid for concentrations up to 4 M,
whereas faster reaction rates occurred with increasing temperature. The effect of chlorine
anions on Ag nanoparticle dissolution, generation of ROS, and toxicity of Ag nanoparticles
has also been investigated, since chlorine anions are the most common anions in aqueous
systems. It was found that high concentrations of chlorine anions facilitate the dissolution
and toxicity of the nanoparticles, because of the formation of Ag−Cl complexes [117]. Ag
nanoparticle toxicity has also been examined for both positive and negative surface charges.
The results revealed that the nanoparticles with positive charge were less toxic to tumor cell
lines, even though they exhibited ion release rates similar to those of negatively charged
nanoparticles. However, the cytotoxicity of Ag nanoparticles is a combination of events,
which include, apart from the surface charge, the release of silver ions, the dissolution rate,
and the activity of biological molecules [128].
Nanoparticles that dissolve in the medium before their uptake by organisms may
have ion channels as a route for cellular entry [96]. The nanoparticles that resist com-
plete dissolution follow other routes to influence the fate of cells, such as endocytosis, ion
transportation, or both. Nanoparticle dissolution may also occur after cell uptake and
inside the cells (intracellular dissolution); this is strongly dependent on the nanoparticle
shape [129]. This dissolution mechanism shows how nanoparticles bypass the good pro-
tection of mammalian cells, as well as how heavy metal ions conduct themselves inside
cells. Copper metal nanoparticles stabilized using a carbon layer were tested for the effects
of nanoparticle dissolution on cytotoxicity and were compared to the behavior of copper
oxide nanoparticles. The influence of pH on the solubility was studied using artificial buffer
solutions of pH 5.5 and pH 7.4. At neutral pH, almost no free copper ions could be detected
after 3 days in the cell culture medium, confirming the stability of the particles. However, at
an acidic pH of 5.5, as found inside lysosomes, the copper oxide particles dissolved rapidly,
whereas the fairly stable carbon-coated copper particles released copper to the surrounding
medium. Thus, intracellular dissolution was attributed to pH effects [99].
Dissolution of nanoparticles is one of the main contributors to particle toxicity. The
dissolution process may occur inside or outside cells. Nanoparticles dissolve mainly by
releasing ions, which are possibly toxic for living organisms. Nanoparticle dissolution can
be affected by the chemistry, size, shape, and surface coating of nanoparticles, as well as
the type of media, the pH, and the solution characteristics of the surrounding environment.
2.3. Hydrophilicity–Hydrophobicity
The hydrophilic/hydrophobic behavior of nanomaterials is mainly associated with
their chemical features, such as composition and surface charge, as well as their surface
coating characteristics, stability, and surface reactivity. The wetting characteristics of
nanoparticles are critical for their biological application [130,131] and are often strongly re-
lated to their biocompatibility and their dispersion and interaction with biomolecules [132].
The hydrophobic interaction is generally thought to be the strongest among all long-range
non-covalent interactions in all aqueous systems, as well as in biological ones. It is advanta-
geous for the adsorption of biomolecules, promotes the interaction and adhesion with cell
membranes by increasing nanoparticle uptake for cellular delivery, and adjusts the release
rate of drugs [133,134].
The modification of the wetting characteristics of a nanoparticle surface can be realized
during either the nanoparticle synthesis or by the post-preparation of surface coatings
on the nanoparticles using appropriate polymers or surfactants. Synthetic procedures
in the presence of block or graft copolymers with hydrophilic segments can lead to hy-
drophilic surface coatings; polymeric surfactants used include poly(ethylene glycol) (PEG),
poloxamers, poloxamines, polysaccharides, and nonionic surfactants, such as polysorbate
80 (Tween 80) [130]. Alternatively, post-preparation coating of the nanoparticle surface
using hydrophilic polymers or surfactants is commonly achieved through chemisorption
or covalent attachment of polymers or surfactants with a functional end-group to a re-
active surface (grafting-to) or by in situ polymerization of monomers from immobilized
initiators onto the nanoparticle surface (grafting-from) [135]. Hydrophilic homopolymers
and copolymers and other coupling agents are also used to affect, both the nanoparticle
morphology, and its surface modification, as well as to introduce specific functional groups
on the nanoparticle surface; these agents can be silane coupling agents, titanate coupling
agents, and organophosphonic acids [136,137].
Among all known nanomaterials, silver nanoparticles exhibit the highest biocompati-
bility and antimicrobial activity. One synthetic method utilizes the thermal reduction of
AgNO3 in the presence of oleylamine as a reducing and capping agent [131]; the adsorption
of oleylamine on the surface of the nanoparticles makes them hydrophobic, as illustrated in
Figure 7. In order to increase the dispersibility of such hydrophobic nanoparticles in water,
a facile phase transfer mechanism has been developed using pluronic F-127, a biocompati-
ble block copolymer [131]. Modifying the Ag nanoparticles surface utilizing PVP allows
the formation of suspensions stable in polar solvents [60], whereas using an amphiphilic
Nanomaterials 2022, 12, 552 surfactant, such as oleic acid, allows suspensions stable in polar solvents, in non-polar 20 of 5
solvents, and in polar/non-polar interface layers [61,62].
Figure 7. (a) The process of modifying the wetting characteristics of Ag nanoparticles from
Figure 7. (a) The process of modifying the wetting characteristics of Ag nanoparticles from hydropho-
hydrophobic to hydrophilic using pluronic F-127 surfactant. (b) Ag nanoparticles before and afte
bic to hydrophilic using pluronic F-127 surfactant. (b) Ag nanoparticles before and after the phase
the phase transfer (Reprinted
transfer (Reprinted with permission
with permission from
from ref. [131]. ref. [131].
Copyright 2010Copyright
Springer). 2010 Springer).
Single
Silica and multi-walled
nanoparticles are carbon nanotubes
well known for (CNTs), with diameters between
their hydrophilicity 0.4 and
and biocompatibility
2 nm, and
However, 2 and
often it is100 nm, respectively,
necessary to makecould
thempotentially be utilizedGenerally,
very hydrophilic. in a wide range of
the presence o
biological and biomedical applications. One of the main technical obstacles for the use of
silanol groups on the surface of SiO2 makes nanoparticles more hydrophilic and
CNTs in these fields is their extremely low dispersibility in aqueous solutions. A number
consequently,
of methods havemorebeen easily dispersible
used to alter the surfacein aqueous
of CNTs, media
in order [142].
to modify their The addition o
wettability
organosilane
and introducecompounds
a hydrophiliccontaining PEG
character, with thechains onto silica
most common being nanoparticles
functionalizationledwithto highly
hydrophilic
hydrophilicand more
polymers easily
[138]. dispersible
Oxidative nanoparticles
acid treatment can introduce [143]. Alternatively,
nanotube-bound car- silica
boxyl acids, thus,
nanoparticles canenabling defect-targeted
be modified withfunctionalization.
other polymers Esterification,
solubleamidation,
in water, ionicsuch a
interaction treatments,
poly(oxyethylene and sidewall-targeted
methacrylate) (POEM) and functionalization
poly(styrene of CNTs are most
sulfonic acid)commonly
(PSSA) [135]. In
realized by surface-attaching hydrophilic polymeric or oligomeric species onto nanotubes.
this case, the process includes three steps: activation of the silanol surface groups of th
PEG, poly(vinyl alcohol) (PVA) and poly(propionylethylenimine-co-ethylenimine) (PPEI-
SiOEI)
2 nanoparticles, surface alteration to chlorine (-Cl) groups, and grafting-from
have been utilized to functionalize SWCNTs. The hydrophobicity of CNTs can also be
polymerization
modified usingof the polymer
non-covalent chains.modification
or covalent The nanoparticles after modification
with carbohydrates (monosaccha- exhibited
better dispersibility
rides compared
and polysaccharides), to the
proteins, andunmodified ones Short
nucleic acids [139]. [135].double-stranded
Furthermore,DNAs polystyrene
and certain RNAs
functionalized silicahave been used to directly
nanoparticles have beendisperse individual
prepared viaSWCNTs
radicalin polymerization
water [140], o
styrene monomer onto nanoparticles possessing vinyl groups, with benzoyl peroxide a
the initiator, resulting in PS-g-SiO2 particles. These PS-g-SiO2 nanoparticles were easily
dispersed in organic solvents such as methylbenzene, whereas when deposited onto a
silicon wafer, they resulted in a superhydrophobic surface [144]. Hydrophilic silica
where the interactions of nucleic acid with the SWCNTs in the aqueous media originate
from the stacking of the bases of the nucleic acids on the nanotube surface with the hy-
drophilic sugar-phosphate backbone pointing towards the solution, to achieve solubility in
water. The use of sodium dodecyl sulfate (SDS) as a dispersing agent allows the preparation
of hydrophilic CNTs. The hydrophobic hydrocarbon segment of SDS interacts with the
CNTs, where the hydrophilic sulfate group causes a high negative surface charge and steric
repulsion that improves the stability of the CNT/SDS dispersion [64]. Hydrophilic MWC-
NTs decorated with magnetic nanoparticles have also been prepared by first synthesizing
poly(acrylic acid)-functionalized MWCNTs (PAA-g-MWCNTs) and then decorating these
with magnetic nanoparticles, utilizing chemical co-precipitation of Fe2+ and Fe3+ onto the
outer surfaces of the PAA-g-MWCNTs; they exhibited an exceptional dispersion ability in
water, as well as high magnetic susceptibility [141].
Silica nanoparticles are well known for their hydrophilicity and biocompatibility.
However, often it is necessary to make them very hydrophilic. Generally, the presence
of silanol groups on the surface of SiO2 makes nanoparticles more hydrophilic and, con-
sequently, more easily dispersible in aqueous media [142]. The addition of organosilane
compounds containing PEG chains onto silica nanoparticles led to highly hydrophilic
and more easily dispersible nanoparticles [143]. Alternatively, silica nanoparticles can be
modified with other polymers soluble in water, such as poly(oxyethylene methacrylate)
(POEM) and poly(styrene sulfonic acid) (PSSA) [135]. In this case, the process includes three
steps: activation of the silanol surface groups of the SiO2 nanoparticles, surface alteration
to chlorine (-Cl) groups, and grafting-from polymerization of the polymer chains. The
nanoparticles after modification exhibited better dispersibility compared to the unmodi-
fied ones [135]. Furthermore, polystyrene-functionalized silica nanoparticles have been
prepared via radical polymerization of styrene monomer onto nanoparticles possessing
vinyl groups, with benzoyl peroxide as the initiator, resulting in PS-g-SiO2 particles. These
PS-g-SiO2 nanoparticles were easily dispersed in organic solvents such as methylbenzene,
whereas when deposited onto a silicon wafer, they resulted in a superhydrophobic sur-
face [144]. Hydrophilic silica nanoparticle surfaces have also been turned hydrophobic with
the addition of alumina sol. The degree of hydrophilicity of the produced silica-alumina
nanoparticles was controlled by changing the proportion of alumina. It was shown that
the nanoparticles modified with 1, 2, and 5% alumina gained 5, 2, and 1% weight in water
compared to the unmodified particles, where the gain was 8% [145].
Production of nanoparticles with hydrophilic composition and hydrophobic properties
at the nanoscale level has been attempted by employing surface topology engineering
(Figure 8). This takes advantage of the fact that surface roughness affects the wettability
behavior. Thus, mesoporous hollow silica (MHS) nanospheres with controlled surface
roughness (rough mesoporous hollow silica, RMHS) have been produced by introducing
silica shell particles with smaller sizes of O(10nm) onto MHS with relatively larger sizes of
O(100 nm). These rough MHS nanoparticles exhibited an unexpected hydrophobicity in
comparison with the respective MHS with no roughness, and this led to higher adsorption
of a range of hydrophobic molecules and the sustained release of hydrophilic drugs [134].
Hydrophobic barium sulfate (BaSO4 ) nanoparticles were produced using a one step
process that combined their synthesis and surface modification [137]. The nanoparticles
were produced by a precipitation reaction of calcium chloride and ammonium sulfate
in a aqueous solution using the modifying agent octadecyl dihydrogen phosphate (n-
C18 H37 OPO3 H2 , ODP). The produced nanoparticles were hydrophobic because of the
formation of a thin layer of barium alkyl phosphates on the nanoparticle surface during
synthesis. It is noted that barium alkyl phosphates control the particle size and morphology
of nanoparticles as well.
wettability behavior. Thus, mesoporous hollow silica (MHS) nanospheres with controlled
surface roughness (rough mesoporous hollow silica, RMHS) have been produced by
introducing silica shell particles with smaller sizes of O(10nm) onto MHS with relatively
larger sizes of O(100 nm). These rough MHS nanoparticles exhibited an unexpected
Nanomaterials 2022, 12, 552
hydrophobicity in comparison with the respective MHS with no roughness, and this led
20 of 47
to higher adsorption of a range of hydrophobic molecules and the sustained release of
hydrophilic drugs [134].
Figure8.8.Morphology
Figure Morphologyofofthe
thesurface
surfaceofofRHMS
RHMSand
and MHS
MHS nanoparticles.
nanoparticles. (a)(a)
SEMSEM image
image of of RMHS, (b)
RMHS,
high-resolution SEM (HRSEM) image of RMHS, illustrating the distances between neighboring shell
(b) high-resolution SEM (HRSEM) image of RMHS, illustrating the distances between neighboring
silica nanospheres, (c) and (d) HRTEM images of RMHS and MHS, respectively. Scale bar = 200 nm
shell silica nanospheres, (c,d) HRTEM images of RMHS and MHS, respectively. Scale bar = 200 nm
(Reprinted with permission from ref. [134]. Copyright 2015 American Chemical Society).
(Reprinted with permission from ref. [134]. Copyright 2015 American Chemical Society).
Hydrophobic
Iron barium sulfate
oxide nanoparticles (BaSO
are of great 4) nanoparticles
importance were produced
in biomedical applications,using a one
such as step
process thatdrug
bioimaging, combined
delivery, their synthesis
cellular andetc.,
therapy, surface
due tomodification
the possibility [137]. The nanoparticles
of surface modi-
were produced
fication and their by lowa precipitation
toxicity [146,147]. reaction
Withofno calcium
surfacechloride
coating,andthe ammonium
surfaces of thesesulfate in
a aqueous solution
nanoparticles using the
are hydrophobic, and modifying
exhibit a large agent octadecyl
surface to volume dihydrogen
ratio [148,149].phosphate
These (n-
particles
C18H37OPO tend3Hto2,agglomerate
ODP). Thebecause produced of hydrophobic
nanoparticles interactions and form large
were hydrophobic clustersof the
because
information
aqueous media,
of a thinwhich
layeralsoof significantly
barium alkyl affects their magnetic
phosphates on the properties.
nanoparticle To surface
overcome during
this, a varietyIt ofissurface
synthesis. notedcoatings
that bariumhave beenalkylemployed
phosphatesto alter the nanoparticle
control the particle surface,
size and
whereas,
morphology for effective stabilization,
of nanoparticles often a very high surface density for the coating is
as well.
required. One approach, is to add
Iron oxide nanoparticles are of great some stabilizer, such as ainsurfactant
importance biomedical or aapplications,
polymer, at the such as
time of preparation, to prevent aggregation of the nanoscale particulates. Alternatively, the
bioimaging, drug delivery, cellular therapy, etc., due to the possibility of surface
particles can be modified after precipitation. Among the most common surface modifiers
modification and their low toxicity [146,147]. With no surface coating, the surfaces of these
are synthetic (e.g., PEG, PVP, PAA, PVA, etc.) or natural polymers (e.g., dextran, chitosan
nanoparticles are hydrophobic, and exhibit a large surface to volume ratio [148,149]. These
and gelatin), fatty acids, polypeptides, and inorganic coatings [150].
particles
Whentend to agglomerate
nanoparticles come because of hydrophobic
into contact with biologicalinteractions
fluids, they andareform large
coated clusters
with
in aqueous media, which also significantly affects their magnetic properties.
proteins within seconds; therefore, cells or tissues almost never interact with the bare parti- To overcome
this,
cles a variety
[151,152]. The ofprotein–nanoparticle
surface coatings have been employed
interactions, which form to alter the nanoparticle
the so-called nanoparticle– surface,
whereas,
protein for effective
‘corona’, stabilization,
have a key often a very
role in nanomedicine highThe
[153]. surface density
proteins forpresent
that are the coating
in is
required.
the plasmaOne approach,onto
are adsorbed is tothe
addnanoparticle
some stabilizer, suchdepending
surface, as a surfactant
on the ornanoparticle
a polymer, at the
time ofcharacteristics;
surface preparation,thisto prevent
is crucialaggregation of the
for their in vivo nanoscale
distribution particulates.
[154]. Alternatively,
The hydrophobicity
ofthe
theparticles
nanoparticles
can beaffects both theafter
modified quantity and the composition
precipitation. Among the of the
most plasma
common proteinsurface
adsorbed
modifiers layer. Nanoparticles
are synthetic (e.g., with
PEG,decreasing
PVP, PAA,surface hydrophobicity
PVA, etc.) were studied
or natural polymers (e.g.,with
dextran,
respect
chitosan to and
theirgelatin),
influence on acids,
fatty plasmapolypeptides,
protein adsorption [155]. Latex
and inorganic particles
coatings [150].with dif-
ferent hydrophobicities were used as model colloidal carriers; it was found that, when
the surface hydrophobicity decreased, the quantity of adsorbed proteins decreased and
the changes in the obtained protein adsorption patterns deteriorated. The hydrophobic-
ity of copolymer nanoparticles (70–700 nm) was controlled via the co-monomer ratio of
N-isopropyl-acrylamide and N-tert-butyl acrylamide (NIPAM/BAM) in the copolymer
synthesis, where the NIPAM-rich particle was the most hydrophilic, and the adsorption
of human serum albumin (HSA) onto these nanoparticles was investigated. The more
hydrophobic nanoparticles were completely covered with a single layer of HAS, whereas
particles with 25% BAM or less exhibited very little binding of HSA [150].
In the fields of nanomedicine and therapeutics, the successful cell uptake of nanoparti-
cles and, consequently, the interaction of nanoparticles with the cell membrane is vital. The
wetting characteristics of nanoparticles play a key role in cell uptake, since their interaction
with the cell membrane depends not only on their shape, surface chemistry, and geom-
etry but also on their hydrophobicity [156,157]. Small molecule nanoparticles (SMNPs),
prepared by self-assembly of π-conjugated oligomers with varying degrees of hydropho-
bicity, were electroporated into live HeLa cells. It was observed that the more-hydrophilic
SMNPs disassembled and dispersed upon cellular uptake cell, whereas the hydrophobic
ones remained intact within the cells [158]. It has been shown that the bioactivity of syn-
thetic nanoparticles can be improved with the introduction of hydrophilic co-monomers
in the hydrophobic segment; the introduction of 2-hydroxyethyl methacrylate in the hy-
drophobic block of a poly(ethylene glycol)-block-poly(α-tocopheryl succinate) reduces the
hydrophobicity of the corresponding nanoparticles and increases their bioactivity [159].
TiO2 nanoparticles, which are used in oral applications, were tested for their wetting be-
havior in relation to their cell–nanoparticle interactions. The viability of epithelial cells,
when in contact with either hydrophobic or hydrophilic nanoparticles, was not affected.
However, the hydrophobic nanoparticles aligned to the cell membrane, wrapped up and
were found in endosomes and lysosomes, while the hydrophilic nanoparticles directly
entered the cells and were found in the cytoplasm [160].
3. How the Key Parameters Affect Functionalities with Respect to Applications

3.1. Cellular Uptake
3.1.1. Mechanisms of Cellular Uptake
Nanomaterials that circulate in a multicellular living organism interact with its com-
ponents in a fundamentally different way compared to the soluble small molecules or
micron-scale particles that are recognized by the immune system [161–164]. Materials
at the nanoscale can interact with the endogenous cellular machinery through active
energy-dependent processes that selectively move substances against their electrochemical
gradient across cell membranes [165–172]. Endocytosis is the mechanism of actively trans-
porting cargoes into the cell in transport vesicles derived from the plasma membrane [165].
The different mechanisms of endocytosis are generally classified as phagocytosis and
pinocytosis. Phagocytosis is the predominant mechanism used mainly by macrophages
and less frequently by nonprofessional phagocytes, including epithelial cells, fibroblasts,
and endothelial cells [173]. Pinocytosis is present in all types of cells, in forms such as
macropinocytosis, which enables the uptake of large NPs that seems impossible via other
endocytosis pathways [174]; caveolae-dependent endocytosis; clathrin-dependent endocy-
tosis; and clathrin- and caveolae-independent endocytosis, with the last three forms referred
to as receptor-mediated endocytosis [175–177]. The phenomena taking place at this nano–
bio interface result in the modulation of cell fate, the induction or prevention of mutations,
the initiation of cell–cell communication, and the modulation of cell structure [178,179].
It has been extensively reported in the literature that the uptake of nanoparticles by
the cells depends on the nanoparticle characteristics, including the size and/or shape,
the surface charge, and surface hydrophobicity [178,180]; on the possible sedimentation
of large and dense particles, on the properties of the protein corona of the individual
nanoparticles [161,162,166,181–188]; and, finally, on the cycle phase of the living cell [189].
The nanoparticle properties mainly designate their endocytosis route, but, in many cases,
the cell can internalize the nanoparticles by utilizing distinct mechanisms, which are also
related to these parameters, as illustrated in Figure 9 [190].
the cells depends on the nanoparticle characteristics, including the size and/or shape, the
surface charge, and surface hydrophobicity [178,180]; on the possible sedimentation of
large and dense particles, on the properties of the protein corona of the individual
nanoparticles [161,162,166,181–188]; and, finally, on the cycle phase of the living cell [189].
The nanoparticle properties mainly designate their endocytosis route, but, in many cases,
the cell can internalize the nanoparticles by utilizing distinct mechanisms, which are also
related to these parameters, as illustrated in Figure 9 [190].
Figure 9. Different cellular internalization mechanisms in relation to the nanoparticle properties,

Figure 9. Different cellular internalization mechanisms in relation to the nanoparticle properties,
such as size, surface functionality, and shape. The cell can internalize the nanoparticles by using
such as size, surface functionality, and shape. The cell can internalize the nanoparticles by using
different mechanisms, taking into account the same parameters [190].
different mechanisms, taking into account the same parameters [190].
The effect of size on the cellular uptake of nanomaterials is a central issue in the field
The effect of size on the cellular uptake of nanomaterials is a central issue in the field of
of Nanobiology [191]. In this context, for the development of suitable cell-tracking and
Nanobiology [191]. In this context, for the development of suitable cell-tracking and drug-
drug-carrier nanoparticle systems, nanoparticle size is considered an important
carrier nanoparticle systems, nanoparticle size is considered an important parameter, since
parameter, since it determines the mechanism and rate of cellular uptake of the
it determines the mechanism and rate of cellular uptake of the nanoparticle and its ability
nanoparticle
to and its ability
permeate through tissuesto[192,193].
permeateAnthrough
equationtissues [192,193].
has been An equation
formulated has been
to calculate the
formulated to calculate the minimum radius of a nanoparticle (R min) required for full
minimum radius of a nanoparticle (Rmin ) required for full wrapping; this Rmin is determined
wrapping;
by thisreleased
the energy Rmin is determined by the energybinding
from the ligand-receptor released(adhesion
from the strength)
ligand-receptor
and thebinding
energy
(adhesion strength) and the energy needed to bend the membrane (membrane
needed to bend the membrane (membrane rigidity). Thus, the dependence of cellular uptake rigidity).
on the nanoparticle size and shape has been extensively investigated [194].
3.1.2. Effects of Geometrical Characteristics on Cellular Uptake

Well-dispersed amorphous silica nanoparticles were utilized to investigate their up-
take, localization, and cytotoxic effects in mouse keratinocytes (HEL-30) [195]. In that study,
the cells were cultured for 24 h using different concentrations of SiO2 nanoparticles with an
30–535 nm average particle size; the cells were assessed for particle uptake and biochemical
changes. TEM analysis revealed that all silica particles were successfully taken up into the
cells independently of size and were localized into the cytoplasm. Moreover, the interplay
between silica nanoparticles of different sizes affecting the cellular uptake with Hela cells
in serum-free medium has recently been reported [196]. When the cells were co-exposed to
silica nanoparticles of different sizes, the bigger nanoparticles significantly promoted the
cellular uptake of the smaller ones, while the smaller nanoparticles inhibited the cellular
uptake of the larger ones. In fact, this was observed, even when the effects of size were
very small or undetectable in the single-exposure experiments.
When surface-functionalized pomegranate-like ferrimagnetic nanoclusters (40–85 nm)

were used in vitro, it was shown that the proliferation of spleenocytes, as well as the
cytokine production, were consistent with the regulation of immune system cells based on
size; it was inferred that small clusters mainly drive immune-stimulatory and inflammatory
responses, while large ones could lead to immune-suppressive and anti-inflammatory
actions [197].
The effects of the size and surface charge of polymeric nanoparticles on cellular uptake
and biodistribution have been investigated [185]. Murine macrophages were found to more
efficiently phagocytose nanoparticles with a large size and high surface charge. Even minor
differences in the size and/or the surface charge of the nanoparticles had a significant
impact on their cellular uptake activating different mechanisms in the endocytosis process.
In vivo biodistribution indicated that 150-nm nanoparticles with small negative charge
showed a tendency to accumulate more efficiently in tumors [185].
The cellular interactions of biologically-active gold nanoparticles as a function of
size in the range of 15–55 nm with alveolar macrophages were evaluated. These cells, as
professional phagocytes, are the first line of host defense in the lungs, and their potential
role in initiating oxidative stress has also been studied. In vitro exposure resulted in
morphologically unusual sizes and adherence characteristics, with significant uptake of
nanoparticles at high doses after 24 h [198].
Significant differences were observed concerning the uptake of colloidal gold nanopar-
ticles of different sizes and shapes [181]. More specifically, the intracellular concentrations
of rod-shaped nanoparticles (74 × 14 nm) differed from those of either 74 or 14 nm spherical
nanoparticles. These results were attributed to the difference in the curvature and the active
surface area between rod-shaped and spherical nanoparticles: the rod-shaped nanoparticles
actually have a larger contact area with the cell membrane receptors than the spherical
ones when the longitudinal axis of the rods interacts with the receptors. An alternative
explanation is related to differences in the distribution of the surfactant molecules adsorbed
on surfaces with different curvatures during the synthesis of the nanoparticles, which may
affect the homogeneity of the serum protein coating and, thus, the effective binding to
receptors [181].
Generally, it is suggested that the receptor–ligand binding constants, the receptor
recycling rates, and exocytosis can be mediated by the size and the shape of the nanopar-
ticles. A significant number of studies have shown that geometry, in addition to the size
of nanoparticles, determines the rate of uptake and, importantly, the uptake mechanism
used by nanoparticles. More specifically, experimental studies using different cell types
have shown that spherical nanoparticles undergo a higher cellular uptake than rod-shaped
nanoparticles [181,182,199]. Moreover, some cylindrical nanoparticles of different mate-
rials, such as carbon nanotubes, iron oxide, and polymers, have demonstrated enhanced
circulation and retention times compared to their spherical counterparts [200–203]. The
in vitro responses of U87 glioblastoma cells to various types of gold nanomaterials (13-nm
spheres, 50-nm spheres, and 40-nm stars) conjugated with siRNA were studied; a much
higher uptake efficiency was observed for the 50-nm spheres and the 40-nm stars when
compared to the 13-nm spheres, as illustrated in Figure 10 [204].
The geometry of nanoparticles appears to also affect the mechanism of their endocy-
tosis. Cellular uptake inhibition experiments indicated that the endocytosis of spherical
silica nanoparticles is mainly carried out by a clathrin-mediated mechanism, while most of
their rod-like counterparts penetrate the cell membrane via macropinocytosis or phagocy-
tosis [205]. However, functionalization of the nanoparticles seems to modify the manner of
their internalization [206,207].
Saturation of the intracellular nanoparticle concentration within hours has been re-
ported [181,208], whereas other reports indicated saturation after several days [209–211].
Moreover, the kinetics and the saturation concentrations were reported to strongly depend
on the nanoparticle dimensions [181]; however, the saturation rate of their uptake seemed
to depend on the number of available free proteins, which are not adsorbed on the nanopar-
different materials, such as carbon nanotubes, iron oxide, and polymers, have
demonstrated enhanced circulation and retention times compared to their spherical
counterparts [200–203]. The in vitro responses of U87 glioblastoma cells to various types
of gold nanomaterials (13-nm spheres, 50-nm spheres, and 40-nm stars) conjugated with
ticle surface in the medium, since these unbound proteins may compete for the receptor
siRNA were studied; a much higher uptake efficiency was observed for the 50-nm spheres
binding sites of the cell surface with those proteins adsorbed on the nanoparticle surface.
and the 40-nm stars when compared to the 13-nm spheres, as illustrated in Figure 10 [204].
Figure
Figure10.10.
Dependence
Dependenceofofthethe yield
yield of cellularuptake
of cellular uptakeandandthethe intracellular
intracellular distribution
distribution of gold
of gold
nanoparticle–siRNA
nanoparticle–siRNA constructs on nanomaterial size and shape. In vitro response of U87 glioblastoma U87
constructs on nanomaterial size and shape. In vitro response of
glioblastoma cellstypes
cells to various to various types of nanoconstructs.
of nanoconstructs. Transmission
Transmission electron microscopyelectron microscopy
(TEM) images (top row)(TEM)
images (top row) and confocal fluorescence microscopy images (bottom row) revealing
and confocal fluorescence microscopy images (bottom row) revealing the 13-nm spheres located
the 13-nm
spheres located within endocytic vesicles, with the 50-nm spheres and 40-nm
within endocytic vesicles, with the 50-nm spheres and 40-nm stars being aggregated, and some being
stars being
aggregated, and some being outside of the endocytic vesicles (yellow arrows in top row). In the
outside of the endocytic vesicles (yellow arrows in top row). In the fluorescence images, the actin
fluorescence images, the actin cytoskeleton and the nucleus were stained with Alexa Fluor 594
cytoskeleton and the nucleus were stained with Alexa Fluor 594 Phalloidin (green) and DAPI (blue),
Phalloidin (green) and DAPI (blue), respectively, whereas the nanoconstructs were labeled with Cy5
respectively, whereas the nanoconstructs were labeled with Cy5 (red) (Reprinted with permission
(red) (Reprinted with permission from Ref. [204]. Copyright 2017 American Chemical Society).
from Ref. [204]. Copyright 2017 American Chemical Society).
The geometry
In order to avoidof complications
nanoparticlesdue appears to also affect
to the sedimentation the mechanism
of nanoparticles of their
in typical
cell cultures,Cellular
endocytosis. upright and
uptake inverted cell culture
inhibition configurations
experiments were utilized.
indicated that the These kind of
endocytosis of
cell experiments illustrate that the cellular internalization of gold nanoparticles
spherical silica nanoparticles is mainly carried out by a clathrin-mediated mechanism, depends on
their most
while sedimentation
of their and diffusion
rod-like velocities and not penetrate
counterparts on their size,the
shape, surface
cell coating, via
membrane
density, and initial concentration. It was also found that more nanoparticles were endocy-
macropinocytosis or phagocytosis [205]. However, functionalization of the nanoparticles
tosed in the upright configuration than in the inverted one, whereas larger differences in
seems to modify the manner of their internalization [206,207].
uptake between the two configurations were observed for nanoparticles exhibiting faster
Saturation of
sedimentation theIt intracellular
rates. nanoparticle
is, therefore, considered concentration
that for in vitro studieswithin hours
with large has been
and/or
reported [181,208], whereas other reports indicated saturation
heavy nanoparticles, sedimentation needs to be taken into serious consideration. after several days [209–
211]. Moreover, the kinetics and the saturation concentrations were reported to strongly
3.1.3. on
depend Effects
the of Surface Charge
nanoparticle and Surface
dimensions Coating
[181]; on Cellular
however, Uptake rate of their uptake
the saturation
seemedExperimental
to depend on andthe
theoretical
numberstudies have investigated
of available the effect
free proteins, which of charge,
are nothydropho-
adsorbed on
bicity, and interfacial forces on the interaction between nanoparticles
the nanoparticle surface in the medium, since these unbound proteins may compete and lipid bilayer for
assemblies, in order to understand the interactions of the nanoparticles with the mem-
the receptor binding sites of the cell surface with those proteins adsorbed on the
brane and the mechanisms that affect their cellular influx, as well as the cytotoxicity and
nanoparticle surface.
inflammatory effects [180,212–215].
In Molecular
order to avoid complications
dynamics simulationsdue to the sedimentation
confirmed that electrostaticof nanoparticles
interactions in typical
dominate
cellover
cultures, upright and
the hydrophobic onesinverted cell culture
when considering configurations
nanoparticles, withwere utilized.
the bilayer withThese
chargedkind of
cellnanoparticles
experimentsinteracting
illustratemore that favorably
the cellular internalization of gold nanoparticles
than their uncharged counterparts. More specifi- depends
on cally,
theirthesedimentation and diffusion
adhesion of anionic nanoparticlesvelocities and not
more strongly on their
influences size, shape,
the membrane surface
struc-
coating, density, and initial concentration. It was also found that more nanoparticles were
ture when compared to cationic nanoparticles, which can promote local disorder in the
area of adhesion, as well as membrane-wrapping phenomena [216,217]. In another study,
computed results indicated that the initial orientation of non-spherical nanoparticles can
be significantly affected by surface charge density; thus, enhancement of the translocation
rate and maximizing the cell adhesion can be achieved by engineering the interplay of
nanoparticle shape and surface charge density [218].
Additionally, a number of experimental studies have elucidated the impact of surface
charge on the interaction between nanoparticles and cell membranes. In agreement with
theoretical models, it has been shown experimentally that cationic nanoparticles strongly
bind to the cell membrane, through electrostatic interactions with the lipid phosphate
groups, increasing the surface tension of the membrane and resulting in the formation of
pores [219]. It has also been reported that negatively or positively charged nanoparticles
preferentially interacting with the choline-phosphate dipole (N+ /P− terminus) of the lipid
membranes, respectively, could cause the surface reconstruction of phospholipid mem-
branes [220]. Charged nanoparticles tend to adsorb more proteins from the serum compared
to neutral nanoparticles [180]. It was demonstrated that large amounts of plasma proteins
were adsorbed on positively- or negatively-charged decorated gold nanoparticles, whereas
relatively few proteins adsorbed onto neutral ones [221]. Mesoporous silica nanoparticles
(MSNs), such MSNs modified with two different silanes, in order to produce mixed-charge
amino-phosphonate pseudo-zwitterionic MSNs under physiological conditions (ZMSN-1.5)
and of PEGylated MSNs were studied with respect to their internalization by flow cytome-
try and laser scanning confocal microscopy experiments. It was shown that cell uptake was
drastically reduced for the functionalized nanoparticles, both for the pseudo-zwitterionic
ZMSN-1.5 and for the PEGylated ones; this is illustrated in Figure 11 [222].
Figure 11. Dependence of the cellular uptake of bare mesoporous silica nanoparticles (MSNs),
pseudo-zwitterionic ZMSN-1.5, and control PEGylated MSNs by RAW 264.7 macrophages. Laser
scanning confocal microscopy images of the nuclei (DAPI), membrane (Phalloidin), and nanoparticle
(FITC) emission channels are shown. Merged images and high magnification merged red-green
channels overlain allow co-localizing the different systems studied. In the co-localization right row
area, selection of region of interest was made with FiJi, marking in yellow the cell membrane border.
Internalized nanoparticles are highlighted with yellow arrows, while those located in the outer
area are marked with white ones (Scale bar: 10 µm, 5 µm for co-localization row) (Reprinted with
permission from Ref. [222]. Copyright 2019 Elsevier).
Molecular dynamics computer simulation has suggested that the insertion of hy-
drophobic nanoparticles could lead to deformation and heterogeneity of the lipid bilayer,
but that this would not cause membrane leakage, while semi-hydrophilic nanoparticles
appear to be energetically absorbed on the surface of the bilayer, thus, inducing their endo-
cytosis [223]. In other theoretical or experimental studies, different nanoparticles were used
to investigate the influence of hydrophobicity on the elastic properties of cell membranes,
on the stability of pre-existing pores in the lipid bilayer, on membrane penetration, and,
therefore, on cell function [224–228].
Surface functionalization of nanoparticles by modifying their surface chemistry, charge,
and hydrophobicity can obviously alter their targeting efficacy and cellular uptake rates.
Indeed, increasing the number of amino groups (–NH2 ), which enhances the positive sur-
face charge, was shown to increase the internalization of nanoparticles into cells. However,
the presence of –COOH functional groups, which increases the negative charge, enhances
their further uptake into the endosomal compartments [229,230]. In different studies, it
has also been reported that functionalized nanoparticles, such as polydopamine function-
alized nanoparticle-aptamer bioconjugates, folic acid-functionalized nanoparticles, and
poly(diallyldimethyl ammonium chloride)-coated gold nanorods, have better targeting
efficacy and higher efficiency of internalization by cells [231–233].
As already mentioned, nanoparticles enter the cells through active processes because
of their ability to interact with the cellular machinery. When the nanoparticles come into
contact with biological fluids, such as the serum of a cell, a selective layer of proteins and
other biomolecules adsorbs on their surface within a few seconds, forming the so-called
corona [234], which mediates, in situ, the interactions with cells. As a consequence, one
nanomaterial may cause a very different biological outcome when exposed to cells in the
presence or absence of a preformed corona. More specifically, silica nanoparticles exhibited
stronger adhesion to the cell membrane and higher internalization efficiency when they
were exposed to cells in the absence of serum, as compared to those in a medium containing
serum, where a corona was formed. The different conditions of exposure not only affected
the levels of uptake but resulted in variation in the location of the intracellular nanoparticles
and their impact on the cells. It is important to note that certain studies showed that, after
just 1-h of exposure, a corona of very different nature can be formed on the nanoparticles
exposed to cells in the absence of serum. This different outcome was attributed to the
different adhesion and surface properties under the two conditions [234]. The protein
adsorption capability is also affected by the nanoparticle properties. For example, both
surface roughening and hydrophobic modification of the nanoparticles enhance the protein
adsorption capacity and affect the cellular uptake performance; however, the relative
importance of the two contributions depends on the cell type [235,236].
3.1.4. Role of Cell Type on Cellular Uptake

The role of cell cycle in the cellular uptake and dilution of nanoparticles in a cell
population has also been investigated, as illustrated in Figure 12 [189,237]. It has been
observed that the cellular uptake of nanoparticles is also influenced by the cell cycle
phase Although more-or-less similar rates of nanoparticle internalization by the cells were
observed for different phases of the cell cycle, after 24 h, the concentration of nanoparticles
in the cells could be ranked according to the different phases, as follows: G2/M > S >
G0/G1, where G0 is the resting phase, G1 is the phase during which the cell increases
its size, S the phase when the cell synthesizes DNA, G2 the one it synthesizes proteins to
prepare for cell division, and M the phase when the cell divides and the two daughter cells
enter the G1 phase. During cell division, nanoparticles that are internalized by the cells
are not exported but are split between daughter cells. Thus, it was indicated that, in a cell
population, the dose of internalized nanoparticles in each cell varied as the cell advanced
through the cell cycle.
Nanomaterials 2022,12,
Nanomaterials2022, 12,552
552 29 27
ofof5147
Figure 12. Dependence of the internalization of ~40 nm carboxylated polystyrene nanoparticles (25
Figure 12. Dependence of the internalization of ~40 nm carboxylated polystyrene nanoparticles
μg/ml in cMEM) in A549 human lung carcinoma cells on the cell cycle phase for exposures up to 72
(25 µg/mL
h. (a): in cMEM)
Confocal in A549images
microscopy human lungcell
after carcinoma
exposurecells on the cell cycle
to nanoparticles phase
for (i) for24,
5, (ii) exposures uphto
and (iii) 72
72 h. (a):
show theConfocal microscopy
nanoparticle imagesinafter
accumulation the cell exposureBlue:
lysosomes. to nanoparticles for (i) 5,red:
cell nuclei (DAPI); (ii) lysosomes
24, and (iii)
72 h showantibody);
(LAMP1 the nanoparticle accumulation in
green: nanoparticles. (b):the lysosomes.
Mean Blue: cell intensity
cell fluorescence nuclei (DAPI); red: lysosomes
as acquired by flow
cytometry
(LAMP1 as a function
antibody); of time.
green: (c): Mean fluorescence
nanoparticles. (b): Mean cell intensities as a function
fluorescence intensityofastime of A549
acquired bycells
flow
in the G0/G1,
cytometry as aSfunction
and G2/M phases,
of time. (c):respectively. (d) Schematic
Mean fluorescence of populations
intensities as a functionofofthe G0/G1,
time S, and
of A549 cells
G2/M
in phases by
the G0/G1, cellsG2/M
S and and consequences for cellular
phases, respectively. (d)NP content as
Schematic of apopulations
function of time
of the(Adapted
G0/G1, S, with
and
permission from ref. [189] and ref. [237]. Copyright 2012 Nature Publishing Group and 2013 Royal
G2/M phases by cells and consequences for cellular NP content as a function of time (Adapted with
Society Publishing.
permission from ref. [189] and ref. [237]. Copyright 2012 Nature Publishing Group and 2013 Royal
SocietyInPublishing.
general, nanoparticles, due to their ability to be endocytosed, cause completely
different cell responses from bulk surfaces of the same material. In spite of what has been
In general, nanoparticles, due to their ability to be endocytosed, cause completely
achieved so far in the materials and nanotechnology fields, a complete understanding
different cell responses from bulk surfaces of the same material. In spite of what has been
from a biological point of view is still missing. In this context, emerging technologies such
achieved so far in the materials and nanotechnology fields, a complete understanding from
as omics, high-throughput screening systems, and organ-on-a-chip technologies, in
a biological point of view is still missing. In this context, emerging technologies such as
synergy with computational approaches, should enable, not only the analysis and
omics, high-throughput screening systems, and organ-on-a-chip technologies, in synergy
documentation of large amounts of data, but also the decoding of nano–cell interactions
with computational approaches, should enable, not only the analysis and documentation
[178,238].
of large amounts of data, but also the decoding of nano–cell interactions [178,238].
3.2. Optical
3.2. Optical and
and Electronic
Electronic Properties
Properties and
and Catalytic
Catalytic Activity
Activity
The nanometer size of manufactured nanomaterials
The nanometer size of manufactured nanomaterials results results in very
in very interesting
interesting andand
very
very important size effects that affect their chemical, structural, thermal, spectroscopic,
important size effects that affect their chemical, structural, thermal, spectroscopic, electronic,
electronic,and
magnetic, magnetic, and mechanical
mechanical properties; properties; these
these effects are oneffects areany
top of on possible
top of any possibleof
influence
influence of the chemistry of their bulk crystals. This is schematically illustrated
the chemistry of their bulk crystals. This is schematically illustrated in Figure 13 [239]. in Figure
13 [239].
Moreover, a single manufactured nanomaterial (MNM) may function differently in
various systems; thus, it is important to carefully design MNMs to develop devices with
enhanced performance, safety, and stability for both humans and the environment. While
material chemistry and nanomaterial size and shape play a significant role in the core
properties of an inorganic nanoparticle, the selection of ligand molecules, which func-
tionalize the surface of the MNMs, is of great significance for their colloidal function and
stability [240]. In this part of the work, a series of studies on the key properties of MNMs
affecting the functionalities relative to applications are discussed; the emphasis is on the
Nanomaterials 2022, 12, 552 electronic and optical properties and the catalytic activity of materials and devices. It is
30 of 51
noted that most functionalities of this type are correlated with the MNM’s key properties.
Figure 13. Schematic comparison between bulk materials and nanomaterials: nanoparticles with
Figure 13. Schematic comparison between bulk materials and nanomaterials: nanoparticles with vary-
varying mechanical, electronic, optical, and magnetic properties, due to their different size and
ing mechanical, electronic, optical, and magnetic properties, due to their different size and shape [239].
shape [239].
3.2.1. Catalytic Properties
Moreover,
Generally,athe single manufactured
catalytic properties ofnanomaterial
nanomaterials are (MNM) may function
far superior compareddifferently
to bulk in
various systems;
materials. thus, it is important
ZnO nanomaterials to carefully
are characterized designcandidates
as possible MNMs to fordevelop devices
transistors, solar with
enhanced performance,
cells, light-emitting safety,
diodes, and stability
sensors, forphotocatalysts,
nano-lasers, both humans and and antimicrobial
the environment.
agentsWhile
becausechemistry
material of their goodandstability, low cost,size
nanomaterial highand
excitation
shape binding energy (60 meV),
play a significant role in wide
the core
band gap (3.37 eV), and widespread availability [241]. Moreover,
properties of an inorganic nanoparticle, the selection of ligand molecules, which ZnO properties could
be enhanced by doping with elements such as Mg [242], Al [243], and Cu [244,245]. In
functionalize the surface of the MNMs, is of great significance for their colloidal function
particular, Cu-doping of ZnO nanomaterials improved the optical properties by creating
and stability [240]. In this part of the work, a series of studies on the key properties of
impurity levels localized in the optical energy band gap [246]. Furthermore, the optical
MNMs
energyaffecting
band gapthe functionalities
is reduced when therelative
average to applications
size are discussed;
of the crystallites the emphasis
decreases, because Cu is
onions
the are
electronic and optical properties and the catalytic activity of materials
incorporated into the ZnO structure [247]. The catalytic activity of ZnO nanomate- and devices.
It rials
is noted
in thethat mostoffunctionalities
presence of this
light has been widely type are for
investigated correlated with applications
environmental the MNM’s key
properties.
(e.g., purification), and this was found to depend on the oxygen vacancies and the mor-
phology of ZnO. Specifically, the photocatalytic performance of ZnO nanodisks for the
decomposition
3.2.1. of methylene blue dye was enhanced because of the higher population of
Catalytic Properties
(0001) crystal plane structures [248]. Furthermore, ZnO nanorods with a cone of small
Generally,
aspect ratio are themore
catalytic properties
effective of nanomaterials
in the photocatalytic are far superior
degradation compared
of organic pollutantsto bulk
materials. ZnO nanomaterials are characterized as possible candidates
than ZnO nanorods with a cone of large aspect ratio and ZnO microrods that are short- for transistors,
solar cells,[249].
and-fat light-emitting
Moreover, ZnOdiodes, sensors,and
nanosheets nano-lasers,
nanoflowersphotocatalysts,
demonstrated aand much antimicrobial
higher
agents because of
photocatalytic their for
activity goodthestability,
degradationlowofcost, high
methyl excitation
orange than ZnObinding energy[250].
nanospheres (60 meV),
The decomposition of volatile organic compounds, such as butane, was
wide band gap (3.37 eV), and widespread availability [241]. Moreover, ZnO properties investigated, taking
advantage
could of the photocatalytic
be enhanced by doping with activity of ZnOsuch
elements nanomaterials
as Mg [242],overAl
multi-channel
[243], and Cu porous
[244,245].
alumina ceramic membranes coated with ZnO nanoparticles, nanorods,
In particular, Cu-doping of ZnO nanomaterials improved the optical properties by and nanowires;
the activity depended strongly on the shape of the nanomaterial used [251]. It was re-
creating impurity levels localized in the optical energy band gap [246]. Furthermore, the
ported that ZnO nanowires showed a higher catalytic activity than ZnO nanoparticles or
optical energy band gap is reduced when the average size of the crystallites decreases,
nanorods and, most importantly, the process did not result in unwanted byproducts such
because Cu ions
as propane, are incorporated
acetaldehyde, into the
and acetylene. ZnO structure
Moreover, [247].
better carbon The catalytic
balance activity of
and selectivity
ZnO nanomaterials
towards carbon oxides inwere
theobtained
presence withofthelight has beenand
ZnO nanowires widely
nanorodsinvestigated
than with for
environmental applications (e.g., purification), and this was found
nanoparticles. ZnO structure, shape, and crystallite size are also important parametersto depend on the
for theirvacancies
oxygen antimicrobialandperformance [252]. ZnOof
the morphology nanoflowers showed enhanced
ZnO. Specifically, photocat-
the photocatalytic
performance of ZnO nanodisks for the decomposition of methylene blue dye was
enhanced because of the higher population of (0001) crystal plane structures [248].
Furthermore, ZnO nanorods with a cone of small aspect ratio are more effective in the
photocatalytic degradation of organic pollutants than ZnO nanorods with a cone of large
alytic activity in Escherichia coli and Staphylococcus aureus inactivation compared to ZnO
nanorods or nanospheres.
The optimization of catalytic performance requires the adjustment of both catalytic
activity and mass transfer. Various bioinspired inner-mobile multifunctional ZnO/CdS
heterostructures have been synthesized, with their artificial cilia mimicking natural ciliary
motion (assisted by external magnetic fields and internal magnetism). Such a synthesis
resulted in a three-times better photocatalytic performance of mobile arrays compared to
static arrays [253].
3.2.2. Sensing Behavior

A bioelectrochemical sensing interface can be engineered with functional nanomate-
rials, so as to develop novel electro-chemical biosensors with enhanced performance in
terms of simplicity, sensitivity, selectivity, and stability [254]. It should be noted that the
use of functional nanomaterials for the development of novel biosensors takes advantage
of nanomaterial properties such as conductivity, high surface area, and improved catalytic
activity; and such properties depend on the size and shape of the nanomaterials, which
control, e.g., the optical properties of metal nanoparticles [255], the electrical conductivity
of the carbon nanomaterials [256], as well as the electrocatalytic properties of nano-carbons
and metal nanoparticles [257], etc.
Carbon nanomaterials (CNMs) exhibit unique electrical, optical, thermal, mechanical,
and chemical properties and are, thus, extensively applied in photovoltaic, electronic,
optoelectronic, and sensing devices. A more recent application of CNMs in the biosensing
field is their use in the area of electrochemical aptasensors (ECASs) [258]. ECASs use
aptamers (short single-stranded oligonucleotides of DNA or RNA), selected through a
systematic evolution of ligands using an exponential enrichment technique (from a random
oligonucleotide library), as recognition elements and exhibit the advantages of low cost,
simple operation, fast response, and high sensitivity. A concentration- or activity-related
electrochemical signal is produced by the transducers as a result of the recognition reaction.
Clinical diagnosis via DNA analysis, immunoassay, or enzymatic sensing, as well as for
environmental monitoring, including ocean and atmospheric pollutants, are the main
detection strategies [258].
The use of carbon nanomaterials significantly increases the detection efficiency of
sensors, in terms of sensitivity, selectivity, and stability, and has become one of the current
development strategies for ECASs-based sensing platforms. The excellent electrical con-
ductivity and high specific surface area of the CNMs allow them to function as electronic
conductive matrices and immobilization platforms for the aptamers [258,259]. These prop-
erties depend on the atomic structures of the different CNMs, such as graphene, graphene
oxide, carbon nanotubes, etc., as well as on their interactions with other nanomaterials,
such as chitosan, silica, or gold nanoparticles. In particular, carbon nanotubes (CNTs) are
commonly used as catalyst carriers or backing layers. CNTs demonstrate an enhanced
electro-catalytic activity and a very large surface area to volume ratio, with multi-walled
carbon nanotubes (MWCNTs) being used more often in ECASs applications than single-
walled carbon nanotubes (SWCNTs). Moreover, combining CNTs with other nanomaterials
(e.g., gold nanoparticles, reduced graphene oxide, dendrimers, chitosan, etc.) can further
enhance the carrier content and stability of enzymes and proteins. Graphene, graphene
oxide, and reduced graphene oxide have also been utilized in ECASs [260,261], with the
main differences in this application originating from their significantly different electrical
conductivities; the effectiveness of these three types of CNMs follows their ranking of con-
ductivities, with graphene being preferable for ECASs development, followed by reduced
graphene oxide and, then, graphene oxide.
Improved device performance and notably enhanced electrical properties were re-
ported when SWCNTs were assembled into aligned arrays with full surface coverage (via
the Langmuir–Schaefer method). The intrinsic mobility of the CNTs was preserved for
a semiconducting nanotube purity of 99% and full surface coverage and, thus, for high
packing density [262].
The use of carbon nanomaterials to construct functional composites was reviewed [263],
and effective methods were presented to achieve light harvesting and conversion, effec-
tive phonon transport along a particular direction, and rapid ion and electron motion in
structural electrodes through the chemical grafting of functional groups to improve their
reactivity and thermal stability [263]. Moreover, novel optical-triggered graphene-based
actuators were fabricated with a bilayer structure including chitosan and polyethylene (PE)
over a large area [264]. The graphene nanosheets played the role of a connecting bridge
between light and the conversion of light energy at the nanoscale.
The hybridization of different types of carbon nanomaterials has been utilized to enable
many different properties and performances beyond that of the individual nanomaterials,
for example in electrochemical or analytical devices. Hybrid nanomaterial systems are,
in principle, designed to develop more efficient sensors. Each nanomaterial exhibits its
own advantages for various applications; thus, it is important to involve synergies due to
the presence of the different nanomaterials, so as to complement each other in the hybrid
system [265,266]. For example, graphene–inorganics composites that take advantage of the
properties of both graphene and the inorganic elements (e.g., gold nanoparticles) enable
even higher active surface areas and enhanced rates of electron transfer. Thus, functional
hybrids are developed based on graphene nanosheets, in order to take advantage of the
electrical, optical, and catalytic properties of graphene and enhance its performance in
analytical chemistry and electrochemistry [256].
MWCNT-modified electrodes have been used to investigate the electrochemical ox-
idation of nicotinamide adenine dinucleotide (NADH) and to elucidate their respective
mechanisms of oxidation [257]; the study compared the behavior with cases when boron-
doped diamond and glassy carbon electrodes were used, as well as with cases when edge
plane and basal pyrolytic graphite electrodes were utilized, which allowed the reactive
sites of carbon nanotubes to be deduced. It was concluded that electron transfer was more
facile with samples containing a higher proportion of edge plane defects, compared to
basal plane graphite electrodes. It was, thus, indicated that electroanalytical sensors with
carbon-based electrodes should optimally possess a large proportion of edge plane sites,
for achieving the best detection limits, whereas edge plane pyrolytic graphite electrodes
can conveniently replace CNT-modified electrodes for routine sensing of NADH, due to
their simple preparation process, low detection limit, low susceptibility to fouling of the
electrode, and insensitivity to interference from ascorbic acid. It was demonstrated that an
electrode produced fully of edge plane graphite (disc of pyrolytic graphite with the disc
surface facing parallel with the edge plane) displayed high levels of electro-catalytic activity
for different electroanalytical tasks, including gas sensing [267] and thiol oxidation [268].
Carbon nanotubes exhibit a quantum electron confinement normal to the nanotube
axis, thus, being able to transport electrons over long lengths [269]. They have great poten-
tial as biomolecule immobilization platforms. According to some studies, CNTs/polymer
nanostructured composites developed on electrodes can improve the analytical perfor-
mance of amperometric biosensors [270,271]. Such composites display percolation behavior,
by remarkably enhancing the electrode conductivity. Moreover, the CNTs thermal and
electrical conductivity and their electrocatalytic activity can be modified by doping of the
CNTs with elements such as K, B, Ce, N, Si, P, etc. [272,273].
Furthermore, multifunctional CNTs offer routes towards the production of smart and
high-performance sensors, logic gates, and similar optoelectronic devices [274]. By combin-
ing CNTs with photochromic molecules, and in particular by decorating them, reversible
changes in the geometrical structure, the electronic properties, and the nanoscale mechanics
triggered by light can be achieved [274]. As a result, there is control of the local variation in
the optical, electrostatic, and mechanical environment with light illumination. For example,
azobenzenes blended with CNTs and polymers are used to form nanocomposites possessing
light-induced conductance switching properties; such nanocomposites are good candidates
for electro-optical memories, smart packaging, and smart window applications [275]. A
graphene/azobenzene/Au heterostructure switch was found to further induce the reversible
modification of the electrical and quantum properties of the Dirac fermions of graphene [276].
Furthermore, a hybrid system of chemically grafted spiropyrans to CNTs was utilized to
regulate horseradish peroxidase (HRP) activity via light illumination. This resulted in en-
hancement of the catalytic activity of HRP and was used as a label-free colorimetric lysozyme
assay with a detection limit of 30 nM. This high selectivity approach can be applied to regulate
the activity of other natural proteins using light [277].
3.2.3. Optoelectronic Properties

Certain nanomaterials are used as biomolecular labels because they exhibit unique
optical properties. They amplify biorecognition signals and enhance the biosensor sensitiv-
ity [269]. Various nanoparticles, including metal, oxide, or semiconductor nanoparticles
and their composites, have been widely used in the fields of biosensors and electrochemical
sensors [278]. The majority of the nanoparticles possess a high isoelectric point (IEP),
favoring electrostatic protein adsorption with low IEP. Thus, they are promising supports
for protein immobilization. A cholesterol biosensor consists of an interfacial layer of gold
nanoparticles, which is used for immobilizing cholesterol oxidase on gold electrode surfaces.
Here, gold nanoparticles provided an environment for the enhanced electrocatalytic activity
of cholesterol oxidase and, thus, improved the stability of the biosensor [279]. The gold
nanoparticles were found to favor the analytical performance of the cholesterol biosensors;
this was attributed to the biocompatibility of the gold nanoparticle-based immobilization
matrices, to assist proteins in retaining their biological activity for long periods and, thus,
improve the stability of the biosensor [269]. The enhancement of the sensitivity and selectiv-
ity of the biosensor was mainly due to the electrocatalytic activity of the gold nanoparticles;
gold nanoparticles improved the conductivity of the electrodes and facilitated the electron
transfer between the electrode and the enzyme redox center. Gold nanoparticles on flat
electrode surfaces may also partially penetrate the enzyme matrix and, thus, come closer to
the enzyme redox center, which further aids the electron transfer pathway.
Interesting nanomaterials include the helical carbon nanofibers (CNFs), with excellent
optical, electromagnetic, and mechanical properties, due to their unique spiral structure;
aiming at applications such as microwave absorbing materials and electrode materials [280].
To improve the optical, physical, mechanical, and chemical properties of CNFs, more func-
tional building blocks were incorporated, to form CNF-based composites. An example is the
in situ synthesized mesoporous N-CNFs containing graphitic-C3 N4 (g-C3 N4 ), in which the
strong coupling between the components of the CNFs enabled the final material to have an
efficient optical storage performance, improved charge separation, and multi-dimensional
electron transport path; thus, improving the performance of hydrogenation production, as
well as the performance in photocatalytic and optoelectronic applications [281].
Another application of gold nanoparticles in the medical field is in cardiac tissue engi-
neering, due to their controlled geometrical, surface, chemical, and optical properties [282].
Additionally, gold nanoparticles enhance the electrical conductivity of nanocomposites.
High electrical conductivity, acceptable biocompatibility, the capability for surface modifica-
tion, nanotopography, and innate optical properties make this nanoparticle type a desirable
nanostructure for cardiac scaffolds [283].
Metal oxide nanoparticles are able to achieve low detection limits in analysis, due
to their electron transfer [284,285]. Moreover, the capability for enhanced adsorption
of the biomolecules leads to high biosensor stability. Cerium oxide (CeO2 ), iron oxide
(Fe3 O4 ), zinc oxide (ZnO), and titanium oxide (TiO2 ) nanoparticles have been exploited for
improving sensor performance [286–288]. Gold nanoparticles exhibit outstanding optical
properties as well; this is due to the surface plasmon resonance (SPR) phenomenon, when
the light interacts with the collective oscillations of electrons on the gold nanoparticle
surface at a certain light wavelength [269]. This depends on the shape, size, and state of
aggregation of the gold nanoparticles. An important application is in the field of detection
zinc oxide (ZnO), and titanium oxide (TiO2) nanoparticles have been exploited for
improving sensor performance [286–288]. Gold nanoparticles exhibit outstanding optical
properties as well; this is due to the surface plasmon resonance (SPR) phenomenon, when
the light interacts with the collective oscillations of electrons on the gold nanoparticle
Nanomaterials 2022, 12, 552 surface at a certain light wavelength [269]. This depends on the shape, size, and 32 ofstate
47 of
aggregation of the gold nanoparticles. An important application is in the field of detection
assays, where an alteration of the light extinction that results from the aggregation of gold
nanoparticles
assays, where upon analyte of
an alteration addition
the lightisextinction
used as thethatoptical signal
results from the[289].
aggregation of gold
nanoparticles upon analyte
The incorporation addition is used
of nanoparticles asvarious
into the optical signal [289].
building blocks within the solar cell
The incorporation
architecture, in order toofenhance
nanoparticles into various
photovoltaic building blocks
performance and within the has
stability, solaralso
cell been
architecture, in order to enhance photovoltaic performance and stability, has also been re-
reported [290]. It was observed that the conversion efficiency of solar cells with silicon
ported [290]. It was observed that the conversion efficiency of solar cells with silicon nanocrys-
nanocrystals was 5.3-times higher than one with only titania (TiO2) particles, contributing
tals was 5.3-times higher than one with only titania (TiO2 ) particles, contributing to further
to light
further light absorption
absorption and, thus, toand, thus, to an of
an improvement improvement
the conversion ofefficiency.
the conversion efficiency.
Further incor-
Further incorporation
poration of nanoparticles
of nanoparticles such as Ag and such
Au,as Ag andvia
produced Au,laser
produced
ablationvia laser ablation
in liquids, into in
liquids, into the active/hole
the active/hole transport
transport layer interfacelayer interface bulk
of P3HT:PCBM of P3HT:PCBM
heterojunctionbulk
solarheterojunction
cells was
solar cells was
reported reported
to lead to lead to
to an enhanced an enhanced
conversion conversion
efficiency [291]. Theefficiency [291].coatings
role of ligand The role of
on nanoparticles in the photovoltaic performance has also been discussed, as
ligand coatings on nanoparticles in the photovoltaic performance has also been discussed, illustrated in
Figure 14 [292].
as illustrated in Figure 14 [292].
Figure 14. Schematic representation of a bulk heterojunction organic photovoltaic cell with three
Figure 14. Schematic representation of a bulk heterojunction organic photovoltaic cell with three
kinds of nanoparticles within the active layer: (i) bare, (ii) TOAB-functionalized, and (iii) P3HT-
kinds of nanoparticles within the active layer: (i) bare, (ii) TOAB-functionalized, and (iii) P3HT-
functionalized. J−V curves of the devices with configurations (a) ITO/PEDOT:PSS/P3HT:PCBM/Al
functionalized. J−V curves of the devices with configurations (a) ITO/PEDOT:PSS/P3HT:PCBM/Al
and (b) ITO/PEDOT:PSS/P3HT:ICBA/Ca/Al, respectively (Reprinted with permission from ref.
and (b) ITO/PEDOT:PSS/P3HT:ICBA/Ca/Al, respectively (Reprinted with permission from
[240], Copyright 2019 American Chemical Society) with the original data from Ref. [292], Copyright
ref. [240], Copyright 2019 American Chemical Society) with the original data from Ref. [292],
2015 American Chemical Society). Nomenclature: ITO: indium tin oxide; PEDOT: poly(3,4-
Copyright 2015 American Chemical Society). Nomenclature: ITO: indium tin oxide; PEDOT:
poly(3,4-ethylenedioxythiophene); PSS: poly(styrene sulfonate); P3HT: poly(3-hexylthiophene-2,5-
diyl); PCBM: [6,6]-phenyl-C61 -butyric acid methyl ester; ICBA: indene-C60 bisadduct.
The chemical, optical, electrical, thermal, and magnetic properties of magnetic nanopar-
ticles can also be exploited in various steps of analytical processes, including sample treat-
ment, chromatographic techniques, and detection [293]. Iron oxides (Fe2 O3 and Fe3 O4 ) and
their corresponding ferrites (e.g., MnFe2 O4 or CoFe2 O4 ) are commonly utilized because of
their biological compatibility, the simple preparation processes, and high magnetic moment
relative to other nanoparticles based on metals and alloys (e.g., Mn3 O4 , Co, Ni, FePt), which
exhibit rapid oxidation in air and/or potential cytotoxicity. Magnetic nanoparticles can
be modified with inorganic, organic, or biochemical compounds to improve their physic-

ochemical behavior. For example, hybrid magnetic nanoparticles are developed by the
combination of Fe3 O4 nanoparticles and carbon, metallic, polymeric, or silica nanoparticles
for the manufacturing of electrodes, thus improving their electrocatalytic properties, among
others [294]. Such electrodes are advantageous, due to their large surface area, low resis-
tance to electronic transmission, and ability to adsorb (bio)chemical analytes, which make
them useful in electrochemical systems. The main advantages of magnetic nanoparticles in
this area are the increase of electrocatalytic activity, the minimization of deterioration of the
electrode surfaces, and the simplification of the immobilization process [293].
Last, we would like to point out that in this mini review we have mostly discussed the
behavior of single nanoparticles, and not nanoparticle assemblies [295]. The formation of
the latter is mostly induced by the very high surface energy of the nanoparticles, because
of their high specific surface area; this provides the driving force for the spontaneous
aggregation of the nanoparticles, which would decrease the Gibbs free energy of the system
and would lead to large assemblies. In these cases, the performance of the nanoparticles for
various applications will be based on the coupling of, and cooperation among, individual
nanoparticles, rather than on their individual properties; this collective behavior would,
of course, depend on the interparticle interactions that would determine their structural
arrangement in space [239]. Such nanoparticle assemblies may lead to a plethora of practical
applications, such as sensing, energy storage, strong materials, catalysis, therapies, etc.
Moreover, introducing different nanoparticles into a superlattice can lead to substitutional
doping when the size of the two types of nanoparticles are similar, in an analogy to the
classical doping process where atomic impurities are intentionally added to a host material
to significantly modify its properties; the electronic properties of such doped superlattices
are significantly influenced by the presence and density of the nanoparticle dopants, leading
to highly tunable nanomaterials [296].
4. Concluding Remarks
Nanotechnology, which deals with the understanding and control of matter in dimen-
sions between about 1 and 100 nanometers and where unique phenomena allow new appli-
cations, has enabled the development of a variety of nanomaterials with unique properties,
aimed at various applications. Thus, it becomes apparent that the interaction of nanomaterials
with their environment is governed by different mechanisms and leads to new responses.
To summarize the main points of this literature review, the key parameters of manu-
factured nanomaterials that play an important role for each of the functionalities are out-
lined below:
The dispersion ability of the nanomaterials is a key issue affecting their behavior.
Nanoparticles form, in general, aggregates and/or agglomerates in water or other aqueous
media; SiO2 nanoparticles are the only exception, where the primary particle size is detected
in certain cases. The dispersion ability is affected by the particle chemical composition,
the existence of an appropriate surface coating, the surface charge, as well as by the
dispersion media, whereas it depends only weakly on their shape and crystallinity. The
particle size is not that crucial in determining dispersibility, except when nanoparticles and
particles with radii larger than 300–400 nm are compared, because of the influence of gravity.
Apart from the nanoparticles themselves, the presence of organic moieties in the solution
(e.g., proteins), the solution pH and its ionic strength affect dispersibility.
The hydrophobicity/hydrophilicity of nanoparticles and other manufactured nano-
materials depends on their chemical characteristics (chemistry, surface charge) and their
surface coating (characteristics, surface reactivity and stability). Besides the effects of
hydrophobicity/hydrophilicity on the dispersibility, with hydrophilic nanoparticles be-
ing more easily dispersed in aqueous media than hydrophobic ones, nanoparticle hy-
drophobicity/hydrophilicity is also very important for their biocompatibility. Hydrophobic
nanoparticles can be rendered hydrophilic by appropriate modification of their surface
using surfactants or various hydrophilic polymers.
Solubility/dissolution of the nanoparticles implicates the release of ions from the

nanomaterials into the solution. It is a function of the nanoparticle characteristics, such as
chemistry, composition, size and surface area, surface coating, and crystallinity. It is also
affected by the pH and the temperature of the solution. The dissolution of nanoparticles
affects their antimicrobial activity and biocompatibility.
The physicochemical properties of nanoparticles, such as size, shape, and surface
properties, control the internalization pathways, thus, playing a pivotal role in cellular
uptake. In biomedical applications of nanoparticles, their coating modification has been
shown to affect the modulation of their cellular internalization. It is important to take into
consideration the possible sedimentation of large and/or dense particles and their diffusion
velocities when in vitro studies are performed utilizing large and/or heavy nanomaterials.
Moreover, the formation of a protein corona on the nanomaterial surface and its composition
play an important role in the possible cellular uptake.
Individual nanomaterials can play various roles in devices in the field of biosensing.
Depending on the desired application, their main key parameters should be designed and
tuned carefully, whereas composite systems are frequently used to enhance the performance
with regards to detection, stability, and duration. The optical and electronic properties
and the catalytic activity of the nanomaterials are functionalities that depend on their size
and shape, whereas the organization of the individual nanomaterials in a hybrid affects the
general performance of the various devices.
All of the above findings are illustrated in the two following Tables. Table 1 demonstrates
how the three functionalities that have been discussed are affected by the main key parame-
ters, whereas Table 2 shows how the key parameters influence the final properties (optical,
electronic, and catalytic properties and the cell uptake). The key parameters discussed have
been grouped into six categories, i.e., as geometrical, chemical, crystallinity, morphological,
coating related, and test medium related parameters. In the tables, we have introduced
the notation of two stars (**) to illustrate that a parameter is a ‘priority’; i.e., it significantly
determines a particular functionality/property, and the notation of one star (*) to illustrate
that a parameter is ‘of importance’; i.e., it is important but it does not determine the behavior
by itself. According to Table 1, it is clear that key parameters like the chemical composition,
the existence of a surface coating, and the test medium are of utmost importance related to
all functionalities, whereas the significance of the others should be deduced case by case. As
far as Table 2 is concerned, it is the size, the shape, the chemical composition, and the surface
charge of nanoparticles that influence, in general, all properties.
One should also point out that an inter-relation exists between the parameters and
the functionalities, and this significantly affects the final properties and, thus, the applica-
tions in which the nanomaterials are used. Moreover, it is noted that the Nanotechnology
Characterization Laboratory (NCL) at the National Cancer Institute USA, which has as-
sessed more than one hundred and thirty different types of nanomaterials, including metal
oxides, fullerenes, liposomes, dendrimers, polymers, quantum dots, and gold colloids,
came to the conclusion that hydrophobicity (which is a ‘functionality’), and size and sur-
face charge (which are ‘key parameters’) are the main factors that influence nanomaterial
biocompatibility [297].
Table 1. How the key parameters of nanomaterials affect performance.
PERFORMANCE
Solubility/ Hydrophobicity/
KEY PARAMETERS Dispersion
Dissolution Hydrophilicity
Particle Size (e.g., hydrodynamic
* ** *
radius and polydispersity index)
Geometrical Shape * ** *
Aspect Ratio * *
Table 1. Cont.
PERFORMANCE
Solubility/ Hydrophobicity/
KEY PARAMETERS Dispersion
Dissolution Hydrophilicity
Composition ** ** **
Chemical
Surface charge/ζ potential ** * *
Crystallinity Crystal structure/Crystallinity *
Topology (e.g., core shell, etc.)
Porosity *
Morphological
Surface area * * *
Roughness * *
Chemistry, Thickness, Topology ** *
Coating Surface Coating Stability ** **
Surface reactivity ** **
Kind ** ** **
Test pH ** ** **
Medium
Ionic Strength ** *
**: a key parameter designated as ‘a priority’ (see text); *: a key parameter designated as ‘of importance’ (see text).
Table 2. How the key parameters of nanomaterials affect their applications.
APPLICATIONS
Catalytic
Cellular Optical Electronic
KEY PARAMETERS Activity/
Uptake Properties Properties
Biorecognition
Particle Size (e.g., hydrodynamic
** ** ** **
radius and polydispersity index)
Geometrical
Shape ** ** ** **
Aspect Ratio ** * * *
Composition ** * ** **
Chemical
Surface charge/ζ potential ** ** **
Crystallinity Crystal structure/Crystallinity * * *
Topology (e.g., core shell, etc.)
Porosity
Morphological
Surface area * * * *
Roughness *
Chemistry, Thickness, Topology ** * * *
Coating Surface Coating Stability * *
Surface reactivity * * * *
Kind ** *
Test
pH *
Medium
Ionic Strength *
**: a key parameter designated as ‘a priority’ (see text); *: a key parameter designated as ‘of importance’ (see text).
5. Challenges and Prospects

In order to advance knowledge in the area of the physicochemical properties/
functionalities of nanoparticles, on how these are determined by their key parameters, and,
more importantly, on how these influence their behavior and their potential to induce, or
not induce, toxicity to both humans and the environment, as well as their ultimate fate more
focused research is still needed in this area. Despite the plethora of related works, there are
still many open challenges with regards to the interrelationships between the physicochemical
main key parameters of nanoparticles and their functionalities, which are considered as very
important aspects for enhancing their safety early on in the design process.
Such challenges include:
• Understanding the interdependence between the bulk properties of the materials
(i.e., in their pristine state) versus the respective properties when the materials exist in
nanodimensions within a particular medium, i.e., dispersed in a biological fluid
• Developing different production/manufacturing routes and different residues
• Understanding and, possibly, modifying different experimental conditions,
e.g., instruments, protocols, in vitro versus in vivo methodologies
• Improving the measuring tools for site-specific or local assessment of nanomaterials,
e.g., high resolution imaging, 3D reconstruction, data acquisition processes
To improve the design of a nanomaterial, one needs to consider the use of innovative
tools to probe the dynamic biophysicochemical interactions. The adoption and optimization
of both theoretical and experimental characterization methods, which are traditionally
utilized for characterizing the properties of bulk materials, for studies of the environment
surrounding nanomaterials and the resulting interfaces is mandatory. This will also be
helped by simple and widely accessible laboratory equipment.
Research is, therefore, needed at the interface of different disciplines, such as engineer-
ing, physics, chemistry, biology, and medicine. This research should aim at the advanced
chemical synthesis of new nanostructures with precisely defined biophysicochemical char-
acteristics and properties, at the development of nanostructures that will replace biological
structures, and at addressing the knowledge gaps concerning the possible health and safety
effects of exposure to manufactured nanomaterials. Such research will be able to give
prominence to nanomedicine as a promising stakeholder in the field of diagnosis, imaging,
treatment, therapeutics, and regenerative medicine.
Author Contributions: Conceptualization, all authors; methodology, all authors; writing—original

draft preparation, K.C., P.K., G.K. and A.R.; writing—review and editing, S.H.A., K.C. and E.S.;
supervision, S.H.A. and E.S.; funding acquisition, S.H.A. and E.S. All authors have read and agreed
to the published version of the manuscript.
Funding: The work was partially supported by the European Union within the NANoREG (Grant
Agreement Number 310584) and NanoReg2 (Grant Agreement Number 646221) projects. Part of
this article was included in Deliverable D.6.6 of project NANoREG and in Deliverable D3.3 of
project NanoReg2.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Data presented in this review article are available from the authors of
the cited publications.
Acknowledgments: We would like to thank Adrienne Sips, Cornelle Noorlander, and Lya Hernandez
of the Institute for Public Health and the Environment (Rijksinstituut voor Volksgezondheid en
Milieu, RIVM), The Netherlands, and Thies Oosterwijk of TNO, The Netherlands, for valuable
discussions. We would also like to thank Tom van Teunenbroek of the Ministry of Infrastructure
and the Environment, The Netherlands, for introducing us to the subject of the NANoREG and
NanoReg2 projects.
Conflicts of Interest: The authors declare no conflict of interest.
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nanomaterials

Received: 17 November 2021 Keywords: physical/chemical characteristics; functionality; nanoparticles; nanomaterials

Publisher’s Note: MDPI stays neutral

Nanomaterials 2022, 12, 552. https://doi.org/10.3390/nano12030552 https://www.mdpi.com/journal/nanomaterials

2. How the Key Parameters Affect Functionalities with Respect to Performance

2.1.1. Dispersibility of Metal and Metal Oxide Nanomaterials

2.1.2. Dispersibility of Carbon Nanomaterials

2.1.3. Surface Modification and Dispersibility

2.1.4. Dispersion Medium and Dispersibility

2.2. Solubility and Dissolution of Nanoparticles

3. How the Key Parameters Affect Functionalities with Respect to Applications

Figure 9. Different cellular internalization mechanisms in relation to the nanoparticle properties,

3.1.2. Effects of Geometrical Characteristics on Cellular Uptake

When surface-functionalized pomegranate-like ferrimagnetic nanoclusters (40–85 nm)

3.1.4. Role of Cell Type on Cellular Uptake

3.2.2. Sensing Behavior

3.2.3. Optoelectronic Properties

be modified with inorganic, organic, or biochemical compounds to improve their physic-

Solubility/dissolution of the nanoparticles implicates the release of ions from the

Table 1. How the key parameters of nanomaterials affect performance.

Table 2. How the key parameters of nanomaterials affect their applications.

5. Challenges and Prospects

Author Contributions: Conceptualization, all authors; methodology, all authors; writing—original

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