Colloidal stability and degradability of silica nanoparticles in biological fluids: a review

Abstract

This review shows the most common and promising strategies to generate colloidally stable silica nanoparticles (NPs) in simulated biological fluids and sheds light on the latest advances in producing degradable silica-based structures. Silica NPs can be synthesized in a wide variety of morphologies, porosity levels, and sizes. This versatility makes silica NPs one of the most promising nano-platforms for imaging and disease treatment. Nonetheless, biological barriers can decrease the success of translating them for therapeutic applications since the media composition can induce their colloidal stability loss. It can, consequently, lead to the NPs aggregation and affect their degradation profile. The interplay between NPs aggregation and degradation has been scarcely explored in the literature when biological fluids are seriously taken into account. Herein we discuss the theory behind the colloidal stability of silica NPs, the processes leading to their aggregation, and some strategies to overcome this issue (mainly focused on NPs surface functionalization). Furthermore, we addressed the main issues that affect the degradability of NPs in biological fluids, and explored some strategies, such as chemical surface modification, which are able to tune these degradation-driven profiles. Thus, the understanding of the silica NPs behavior in body fluids is essential for the approval of nanomedicines and, therefore, more investigations concerning the dynamics, thermodynamics, biological response, and structural parameters of silica-based NPs are of utmost importance.

Full text

Journal of Sol-Gel Science and Technology
https://doi.org/10.1007/s10971-021-05695-8
INVITED REVIEW: SOL–GEL AND HYBRID MATERIALS FOR BIOLOGICAL
AND HEALTH (MEDICAL) APPLICATIONS
Colloidal stability and degradability of silica nanoparticles in
biological fluids: a review
Andressa da Cruz Schneid1●Lindomar Jose Calumby Albuquerque1●Gabriela Borba Mondo1,2 ●Marcelo Ceolin3●
Agustin Silvio Picco3●Mateus Borba Cardoso 1,2
Received: 14 May 2021 / Accepted: 18 November 2021
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022
Abstract
This review shows the most common and promising strategies to generate colloidally stable silica nanoparticles (NPs) in
simulated biological fluids and sheds light on the latest advances in producing degradable silica-based structures. Silica NPs
can be synthesized in a wide variety of morphologies, porosity levels, and sizes. This versatility makes silica NPs one of the
most promising nano-platforms for imaging and disease treatment. Nonetheless, biological barriers can decrease the success
of translating them for therapeutic applications since the media composition can induce their colloidal stability loss. It can,
consequently, lead to the NPs aggregation and affect their degradation profile. The interplay between NPs aggregation and
degradation has been scarcely explored in the literature when biological fluids are seriously taken into account. Herein we
discuss the theory behind the colloidal stability of silica NPs, the processes leading to their aggregation, and some strategies
to overcome this issue (mainly focused on NPs surface functionalization). Furthermore, we addressed the main issues that
affect the degradability of NPs in biological fluids, and explored some strategies, such as chemical surface modification,
which are able to tune these degradation-driven profiles. Thus, the understanding of the silica NPs behavior in body fluids is
essential for the approval of nanomedicines and, therefore, more investigations concerning the dynamics, thermodynamics,
biological response, and structural parameters of silica-based NPs are of utmost importance.
These authors contributed equally: Andressa da Cruz Schneid,
Lindomar Jose Calumby Albuquerque, Gabriela Borba Mondo
*Agustin Silvio Picco
apicco@inifta.unlp.edu.ar
*Mateus Borba Cardoso
cardosomb@lnls.br
1Laboratório Nacional de Luz Sincrotron (LNLS), Centro Nacional
de Pesquisa em Energia e Materiais (CNPEM), CEP 13083-970,
Campinas, SP, Brasil
2Instituto de Química (IQ), Universidade Estadual de Campinas
(UNICAMP), CEP 13083-970, Caixa Postal 6154, Campinas, SP,
Brasil
3Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas
(INIFTA-UNLP-CONICET), 1900 La Plata, Argentina
1234567890();,:
1234567890();,:

Graphical Abstract
Keywords Silica nanoparticles ●Colloidal stability ●Aggregation ●Degradation ●Biological fluids
Highlights
●We discuss the challenges faced by silica-based nanoparticles in biological media.
●We address relevant strategies to avoid aggregation of silica nanoparticles in biological fluids.
●We present the impact of media and particle characteristics on silica nanoparticles degradation.
●We discuss strategies used to tune silica nanoparticle degradability in the biological environment.
1 Introduction
Silica nanoparticles (NPs) have emerged over the last few
decades as a promising nanoplatform for diseases treatment
and diagnosis [1–4]. Tailoring silica NP properties allows
the production of a limitless range of nanostructures, mak-
ing them a versatile platform that can be fine-tuned to dis-
tinct applications [5]. They have been engineered for
medical purposes into different structures, including non-
porous [6–8], mesoporous [9–11], and hollow silica NPs
(MSNs and HSNs, respectively) [8,12,13], as schematized
in Fig. 1a. Fundamental knowledge on the synthesis,
sol–gel chemistry, and physical chemistry of silica nanos-
tructures has been extensively documented in classical
books such as the ones authored by Iler [14], and Brinker
and Scherer [15], or edited by Bergna and Roberts [16]. The
ultimate design of these particles is engineered to fulfill
specific nanomedicine purposes since each system presents
unique structural properties and [5,17,18] results in dif-
ferent biological media responses [19–21]. Non-porous
silica NPs are among the most efficient platforms to eval-
uate the influence of surface functionalization in biological
environments [22,23] while MSNs and HSNs can entrap
high therapeutic loads for drug delivery applications [5,19].
Silica surfaces can also be found in composite structures as
a shell surrounding cores of metallic NPs (e.g., gold),
magnetic NPs (e.g., SPIONs), or quantum dots, among
other materials [4,18,24]. These core@shell nanostructures
benefit from several well-known silica functionalization
routes and the biocompatibility of silica-based materials
[25,26].
The use of silica in the biomedical field seems evident
since it is already part of the daily human diet throughout
freshwater, seafood, grains, and vegetable consumption
[27]. After ingestion, silicon-based compounds reach the
bloodstream, where a fraction is adsorbed as silicic acid (the
main product of silica degradation), while the remaining
portion (ca. 41%) is excreted in the urine [27,28]. In 2010,
silica was accepted as “Generally Recognized As Safe”by
the US Food and Drug Administration (FDA) and has been
used in cosmetics and FDA-approved food [5,27]. None-
theless, this safeness cannot be directly extrapolated to the
NP form of silica, since they can trigger different body
responses depending on their structural properties and sur-
face functionalization [3,21]. In this context, the approval
of Cornell dots (C-dots) for clinic imaging trials by the FDA
in 2014 was a milestone for the silica-based NPs research
[5,29], boosting the studies using this platform for treating
diseases (cancer, bacteria, and virus infection) and imaging
diagnostics [5,30–32]. Recently, the approval of Sebacia
and AuroLase for the treatment of severe inflammatory acne
vulgaris and solid tumors, respectively, highlighted the
potential of inorganic-based silica-containing nanomedi-
cines [33].
Journal of Sol-Gel Science and Technology

The medical potential of silica-based nanomaterials has
been widely demonstrated in simple fluids, such as water
and buffers. However, their physicochemical properties and
designed biological activity might considerably change
when exposed to complex media [21,34]. The high ionic
strength combined with the adsorption of biomolecules
(mainly proteins) from biological environments can trigger
silica NPs’aggregation and degradation (Fig. 1b) [20,35].
The aggregation process can impair silica NPs functionality
altering their interaction with cells and tissue components
[36]. The loss of colloidal stability has a profound impact
on NPs’biological behavior, which can reduce cellular
uptake, targeting, and drug delivery efficiency while pro-
moting early silica NPs clearance from the bloodstream
[37]. Alongside aggregation, silica NPs also face degrada-
tion as a major challenge when exposed to biological media.
Degradation is a spontaneous and uncontrollable process for
bare silica NPs that can enhance their clearance from the
body, impacting their ultimate efficiency as a drug-carrier
and bioaccumulation profile [20]. On the other hand, silica
NPs’degradation in biological media can be explored as a
beneficial process, which can be used to control drug release
into a desired site of action. For this purpose, the doping of
silica NPs’structure with organosilane precursors, metal
ions, and oxides has been explored to modulate their
degradation rate under a given stimulus (e.g., light, pH, and
enzymatic attack) [2,27].
In addition to the aggregation and degradation processes,
the contact of silica NPs with biofluids, such as plasma,
which is rich in proteins and other biomolecules, can also
lead to their adsorption onto NP surface, forming the so-
called protein corona (PC). The PC modifies the chemical
identity of the NPs’surface, affects their colloidal stability,
changes NPs’interaction with biological components, and,
consequently, alters their fate and ultimate performance
[38]. Thus, different functionalization approaches have been
explored to overcome protein adsorption, preserve colloidal
stability, and tune the degradation of silica NPs [39,40].
Among various methods [8,41,42], silanization using
alkoxysilanes (mainly trialkoxy derivatives; see Fig. 1c) is
the most used strategy for silica NPs’surface modification.
Hydrophilic polymers such as polyethylene glycol (PEG)
Fig. 1 Schematic representation of athe silica NPs families with desirable properties for nanomedicine application, bthe possible outcomes of
silica NPs in biological environment, and cthe main strategy for functionalizing silica NPs surface using organo(trialkoxy)silanes
Journal of Sol-Gel Science and Technology

and zwitterionic compounds, as sulfobetaine moieties, for
instance, have been applied to enhance colloidal stability
and prevent unwanted silica-based NPs degradation
[40,43]. Multiple responses (protection against aggrega-
tion, targeting, responsiveness to media conditions, and
degradation rates tuning) often require the use of multiple
functional agents onto NPs’surface, each one providing a
specific effect or acting as an anchor point for further
modifications. For instance, targeting groups such as folic
acid, boronic acid derivates, and a wide range of antibodies
have been used to direct silica NPs toward tumor cells and
bacteria [44–47].
While PC formation has been widely explored and
reviewed in the literature [48,49], the understanding of
colloidal stability and degradation rate in body and complex
fluids has been considerably neglected and poorly docu-
mented. It is noteworthy to mention that the discrepancy of
the media complexity in aggregation and degradation tests
still precludes the complete comprehension of the system
behavior, which requires the evaluation of both processes
under the same medium stimuli. While researchers have
designed silica NPs to overcome aggregation in a complex
biological milieu (e.g., cell culture media and blood plasma)
[19,35,50], the degradation mechanism has been primarily
described in much simpler environments, such as simulated
body fluids (SBF) [28,38,51]. We here discuss silica-based
nanostructures’fate within this scenario, focusing on the
aggregation and degradation of these NPs in different bio-
logically relevant media. Table 1summarizes the chemical
composition of some selected media mentioned along with
this review. We aim to provide the reader with a clear
picture of some of the main challenges silica-based nano-
medicines face nowadays in their translation to clinics and
potential solutions to overcome them.
2 Colloidal stability of silica nanoparticles in
biological fluids
2.1 Basics on the colloidal stability of silica
nanoparticles
Aggregation affects the diffusion, gravitational settling, and
the available NPs’surface. Thus, it obviously alters the
interactions of the particles with cellular and tissue com-
ponents, ultimately modifying biological outcomes such as
cellular uptake, immune-biocompatibility, and toxicity of
NPs [39,52–54]. Hence, understanding and controlling
NPs colloidal stability are of paramount importance. Tra-
ditionally, NPs colloidal stability in aqueous electrolyte
solutions is interpreted and quantified using the
Derjaguin–Landau–Verwey–Overbeek (DLVO) theory
[55–57]. In its original formulation, DLVO theory models
colloidal interactions of likely-charged particles as the sum
of two opposing forces: attractive van der Waals (vdW) and
repulsive electrostatic (ES) forces (see Fig. 2a). vdW forces
are short-ranged interactions that result from the interaction
between permanent dipoles (Keesom Forces), permanent
and induced dipoles (Debye Forces), and induced dipoles
(London Forces). For colloids (diameters above ~0.5 nm),
vdW forces usually decay with the first or second power of
the interparticle distance depending on the shape of the
interacting particles. A key parameter for quantifying/esti-
mating the vdW forces between NPs in a given medium is
the effective Hamaker constant, which depends on both the
material and solvent nature. Details on the determination of
Hamaker constants and selected values for inorganic
materials, in particular for the silica-based ones, can be
found in references [58] and [59].
In aqueous media, most NPs present surface charge due
to the dissociation/ionization of surface groups and the
adsorption of charged molecules/ions [55]. In the case of
silica surfaces, they are negatively charged due to the dis-
sociation of silanol groups as explained below. The surface
charge is balanced by counter-ions forming a cloud around
the particle. The classical electrical double layer (EDL)
model describes the ionic cloud as being constituted by two
regions: (a) the Stern layer, composed of approximately a
plane of adsorbed counter-ions, and (b) the diffuse layer
where the concentration of counter-ions gradually decreases
until reaching bulk electroneutrality (see Fig. 2b). The plane
separating these two layers is known as the Stern plane.
More important from an experimental point of view is the
shear plane (or slipping plane), at a distance where ions are
no longer bound to the particle. It is challenging to locate
this plane precisely, and it is usually thought to be inside the
diffuse layer but close to the Stern plane. The potential at
this plane is the measurable ζ-potential, an essential indi-
cator of colloidal stability (or the lack of it). A repulsive
force is generated when EDLs of two similar particles
overlap due to the osmotic pressure from the difference in
ion concentration between the mid-plane of the overlapping
EDLs (higher) and the media bulk (lower).
The ES repulsions are long-ranged and, for colloids,
experience an exponential decay with distance. Besides
the nature of particle surface groups, the most critical
(media) parameters influencing ES repulsions are pH and
electrolyte concentration (or, most precisely, the ionic
strength). The pH determines the degree of ionization of
dissociating surface groups. For acidic groups (e.g.,
COOH, or silanol groups from silica), higher pH leads to
a higher ionization degree and, consequently, a higher
negative surface charge, resulting in a greater ES repul-
sion between similar particles. The opposite trend is
observed for surfaces containing basic groups (e.g.,
NH2), where lower pHs lead to higher positive surface
Journal of Sol-Gel Science and Technology

charges and greater ES repulsions. On the other hand,
electrolytes in solution produce a screening effect on the
ES forces, and at high ionic strength, the particle EDL is
compressed, promoting a reduction of the interparticle ES
repulsion that ultimately may lead to the loss of colloidal
stability. In addition, the greater the electrolytes’valency,
the higher the colloidal destabilization they generate
(Schulze-Hardy rule) [57,60].
Table 1 Chemical composition
of selected biologically relevant
media used for the testing of
colloidal stability and
degradation of silica NPs
PBS SBF FaSSGF FaSSIF SLF ALF DMEMa
10% FBS
RPMIa
10% FBS
pH 7.4 7.4 1.6 6.5 7.4 4.5 7.4 7.4
Na+b(mM) 157 142 34.2 134.3 143.5 208.9 155.3 124.3
K+(mM) 4.5 5 4 5.33 5.33
Ca2+(mM) 2.5 2.5 0.87 1.8 0.42
Mg2+(mM) 1.5 1 0.53 0.81 0.41
Fe3+(mM) 0.25
Cl-b (mM) 139.7 148.8 59.2 105.7 114 57.7 117.5 100.2
HCO3
−(mM) 4.2 31 44.0 23.8
SO4
−(mM) 0.5 0.5 0.27 0.81 0.41
HPO42−(mM) 11.8 1 28.6 1 0.5 0.92 5.63
NO3
−(mM) 0.74 0.85
TRIS (mM) 50
Acetate (mM) 7
Citrate (mM) 0.33 108.5
Tartrate (mM) 0.39
Lactate (mM) 0.76
Pyruvate (mM) 0.78
Glycine (mM) 0.79
Amino acidsc(mM) 10.6 6.44
Vitaminsc(mM) 0.15 0.24
Proteinc(g/L) 3.5–5.5d3.5–5.5d
Albumin (g/L) 1.7–3.5d1.7–3.5d
Glucose (mM) 25e11.1
Taurocholate (μM) 80 3000
Lecithin (μM) 20 750
Pepsin (g/L) 0.1
DPPC (mM) 0.27
The values informed where collected from references [180] (SBF, FaSSGF, FaSSIF, and ALF) [181] (SLF),
and [35] (DMEM +10% FBS and RPMI +10% FBS). In addition to FaSSGF and FaSSIF, simpler versions
(known as simulated gastric and intestinal fluids, SGF and SIF, respectively) and versions emulated fed-state
are used to study the fate of silica NPs. Information on these media can be found in the references previously
mentioned
PBS phosphate buffer saline, SBF simulated body fluid, FaSSGF fasted state simulated gastric fluid, FaSSIF
fasted state simulated intestinal fluid, SLF simulated lung fluid, ALF artificial lysosomal fluid, DMEM
Dulbecco’s Modified Eagle Medium, RPMI Roswell Park Memorial Institute medium, TRIS tris
(hydroxymethyl)aminomethane, DPPC dipalmitoylphosphatidylcholine
aThe versions of DMEM and RPMI supplemented with FBS are shown in this table. Non-supplemented
DMEM and RPMI are also used in the testing of NP colloidal stability and degradation. In these latter cases,
the composition is almost the same but without the constituents coming from FBS (e.g., proteins among
others)
bSince the pH in most of these media is adjusted using HCl or NaOH, the concentrations of Na+and Cl-may
slightly vary after pH adjustment
cRefers to the total content of vitamins, free amino acids, and proteins
dThese values depend on FBS batch and distributor
eThis concentration is used in the “high-glucose”version of DMEM. Moreover, depending on the version,
DMEM can also contain, pyruvate, HEPES buffer, among other constituents
Journal of Sol-Gel Science and Technology

In NPs having acid–base titratable surface groups, like
those exemplified in the previous paragraph, the surface
charge depends on media pH. Therefore, the point of zero
charge (PZC), the pH at which the colloid surface has zero
net charge, is of fundamental importance [61]. The PZC of a
NP is usually measured through potentiometric (acid–base)
titrations. On the other hand, the isoelectric point (IEP) is
the pH at which the particle ζ-potential is zero and can be
interpreted as the PZC at the slipping plane [62]. At the IEP,
particle diffusion is no longer influenced by the presence of
an electric field. Different from PZC, the IEP of a NP is
derived from electrokinetic methods. Although these terms
are frequently used interchangeably, strictly speaking, they
are equivalent only when specific ion adsorption is absent
[63]. Values of IEP and PZC of different solid hydroxides
and oxides (including silica) can be found in the seminal
and pioneering review by Parks in the 60s [64]. More
recently, Kosmulski has revisited and updated Parks’work
[65].
Although the original DLVO theory is a milestone for
colloidal physical chemistry, it is frequently unable to
explain the colloidal behavior of NPs with more complex
surfaces and surrounding media. For instance, decoration of
NPs surfaces with synthetic polymers may enhance NPs
resistance toward aggregation due to steric repulsion [66].
On the other hand, cell culture media and plasma present
complex ion composition (including divalent ones) and a
plethora of large (e.g., proteins) and small (e.g., carbohy-
drates, lipids, vitamins) molecules that may alter NP col-
loidal stability. Taking proteins as an example, their
adsorption onto NPs may lead to stabilization due to steric
or electrosteric repulsions or induce aggregation due to
surface neutralization or bridging interactions [35,67].
Then, various extensions of the DLVO theory have been
proposed to account for these other repulsive (e.g., steric,
hydration) and attractive (e.g., hydrophobic, depletion)
interactions [56,68,69]. As discussed below, the silica NPs
colloidal behavior, even in aqueous suspensions, cannot be
fully described by DLVO theory.
Bare silica NPs exhibit IEPs around pH ~2–4[65], and
at pH > IEP are negatively charged when in aqueous
media. The negative charges arise from the proton dis-
sociation of surface acidic silanol groups (≡Si-OH →≡
SI-O-;seeFig.3a), and the pKa reported for this reaction
rangesfrom4to7.5(mostfrequentlyaround6–7) [70–
73]. Differences in both IEP and pKa values are attributed
to the silica NP nature and the evaluation method [73].
Silanol groups at the silica surface can be classified
depending on the proximity to other silanols and the
number of -OH groups linked to the silicon atom (see Fig.
3a). Experimentally, from titrations at varying pH, two
silanol groups have been detected, with pKa values
around 4.5–5.5 (constituting 15–19% of the total) and
8.5–9.9 (81–85%) [74,75]. These observations are fur-
ther confirmed by ab initio molecular dynamic simula-
tions that show the presence of isolated silanol and
interacting silanol groups with pKa values ca.9–10 and
2–3, respectively [76]. In addition, another acid–base
equilibrium takes place on silanol groups involving the
protonation of neutral ones (≡Si-OH →≡Si-OH2+;see
Fig. 3)[71,73], and the pKa for this reaction is estimated
between −1.8 and −1. Finally, the silica NPs surface also
presents siloxane groups (Si-O-Si, see Fig. 3b). Unlike
silanols, which can act as hydrogen bonding acceptors or
donors [77], siloxanes are weak hydrogen acceptors [78].
Thus, higher silanol contents induce higher silica surface
Fig. 2 aSchematic representation of interaction potential energy vs
surface distance profiles according to the classic DLVO theory. “Net-
DLVO”stands for the overall potential energy (summation of elec-
trostatic repulsion and van der Waals attraction terms). bSchematic
representation of electrical double layer (EDL) model presenting the
different planes and potentials involved. The inset depicts the origin of
the (negative) charges in silica surfaces (silanol groups)
Journal of Sol-Gel Science and Technology

hydrophilicity. Contrarily, high siloxane content makes
silica surfaces more hydrophobic.
The colloidal behavior of bare silica NPs suspended in
aqueous electrolyte solutions is frequently described as
“anomalous”since the regular DLVO theory cannot explain
the different regimes observed. Figure 4is adapted from
experimental published data and presents the influence of
pH and sodium chloride on the silica NPs colloidal behavior
(in this case, the tendency to coagulate) [79,80]. At high
salt concentrations (Fig. 4a), silica NPs are stable at low pH
and coagulate at pH above 8. Also, the critical coagulation
concentration (CCC) in NaCl solution decreases with the
pH increasing in the range of 6–12 (Fig. 4b). Following
DLVO theory predictions, the opposite trend is expected in
the data shown in Fig. 4since the ionization of silica surface
is likely larger at higher pH and increases the NP stability
due to ES repulsion. Moreover, at low pH (around the IEP),
where no ES repulsion is present, silica NPs are very stable
and tolerate high salt concentrations without any aggrega-
tion signal.
Different hypotheses have been postulated to explain the
anomalous colloidal stability of silica sols considering
short-range repulsive interactions. The formation of a “hairy
layer”of polysilicilic acid chains (see Fig. 5a) at the silica/
water interface has been proposed as a source of stability in
silica NPs [81–83]. In this case, a steric repulsion is gen-
erated when such layers overlap and, thus, counterbalance
the attractive vdW forces. On the other hand, the formation
of a hydration layer (see Fig. 5a) over silica surfaces (as
thick as 4–5 nm) leads to strong hydration repulsive forces
and has been considered as the possible mechanism behind
the stability of silica colloids [84,85]. Regardless of the
mechanism, surface silanols likely play a pivotal role in this
silica NPs anomalous stability since the reduction of silanol
surface density (by dehydroxylation and formation of sur-
face siloxanes or by surface silanization) [86,87] makes
silica NPs behave more following DLVO theory.
2.2 Colloidal stability of silica nanoparticles in
biologically relevant fluids
Colloidal stability of silica-based NPs has been inten-
sively studied in a plethora of different biologically
relevant media such as cell culture media (e.g.,DMEM
and RPMI) with or without fetal bovine serum (FBS),
buffer solutions containing selected proteins (e.g.,bovine
serum albumin, BSA) and diluted human plasma or
serum. The composition of selected media can be found
Fig. 4 aTurbidity measurements (at λ=280 nm) of silica nanoparticle
(diameter ~54 nm) suspensions in the presence of 1.5 M NaCl at
varying pH. bCritical coagulation concentration of NaCl for silica
nanoparticles at different pHs (Ludox AM, diameter ~15 nm). In a,γ
refers to the extinction coefficient (roughly, higher γindicates a more
coagulated sample). In b, the CCC at different pHs was determined by
following the suspension Rayleigh ratio at 45° (at λ=546 nm) and it is
expressed in the graph as the logarithm of the salt concentration
required to coagulate the sample. In both cases, the values obtained in
basic condition (pH > 9–10) should be taken with caution since
degradation also takes place at this pH range, as discussed in the next
section. aand bwere adapted from Depasse et al. [79] and Allen et al.
[80], respectively, with permission from Elsevier [199]
Fig. 3 Schematic representation of aacid–base equilibrium of surface
silanols and bmolecular structures of different silanols and
siloxane groups
Journal of Sol-Gel Science and Technology

in Table 1presented in the previous section. The majority
of the studies have shown that bare non-porous silica NPs
tend to be relatively stable in non-supplemented DMEM
[37,52,88–92]andRPMI[37,39,93], but are prone to
aggregate in the presence of FBS. In the latter case, large
NPs seem to be slightly more stable than the smaller ones.
For instance, bare silica NPs of 20 and 30 nm aggregated
in FBS-supplemented DMEM, while those of 110 nm
remained stable with only a slight increase in their
hydrodynamic diameters, which is attributed to PC for-
mation [91]. Similar results were observed when the
colloidal stability of 50 and 500 nm silica NPs was
investigated in RPMI with 10% FBS. Moreover, the silica
NPs colloidal stability has also been compromised in
supplemented media in rarely used cell culture media,
like EMEM [94]orHam’sF-12[92].
In protein solutions, silica NPs exhibit different colloidal
behaviors depending on the protein identity. For instance,
severe aggregation is observed after silica NPs incubation
with lysozyme (pI =11.4; positively charged at physiolo-
gical pH) [67,95,96]. This phenomenon has been attributed
to NP surface neutralization after lysozyme adsorption onto
silica NPs surfaces, thus, eliminating ES repulsion and
bridging interactions between NPs. In PBS solution con-
taining albumin (e.g., BSA), silica NPs tend to aggregate
with time regardless of size [26,97]. However, colloidally
stable mixtures of silica NPs and BSA were obtained when
buffers of lower ionic strengths than PBS were used (e.g.,
phosphate buffer without added salt) [98]. Conversely,
different trends have been observed when silica NPs were
exposed to plasma, depending on NP size, plasma con-
centration, and incubation time [26,36,99,100]. For
example, silica NPs of 200 nm were considerably stable in
solutions containing plasma from 3 to 80% v/v [99]. These
NPs exhibited a decreased ζ-potential after plasma incuba-
tion that was attributed to an adsorbed protein layer. Simi-
larly, good colloidal stability of 100 nm silica NPs was
observed in high serum contents (above 30% v/v), although
aggregation was observed when these particles were incu-
bated in low serum contents (10% v/v) [100]. Aggregation
of 35, 120, and 140 nm silica NPs has also been reported in
plasma after 30 min of incubation, although they remained
stable in shorter times [36]. Rapid aggregation was found
when smaller silica NPs (~23 nm) are incubated in PBS
with 25% v/v human serum [26].
MSNs have been shown to be less colloidally stable than
their non-porous counterparts [93,101]. They tend to
aggregate in buffers under physiological ionic strength
conditions like PBS [102] and HEPES saline (HBS, con-
taining NaCl 150 mM) [103] or SBF [104,105]. Contrast-
ing results have been seen in FBS-supplemented media
(DMEM, RPMI, HBS), which is somehow similar to what
has been discussed above for non-porous silica NPs. Thus,
while some of the MSNs aggregated in the presence of FBS
[102], others remained stable [103], likely due to protein
adsorption. Table 2compiles the main results from selected
works devoted to the colloidal stability of non-
functionalized and functionalized silica NPs. The influ-
ence of surface functionalization on the colloidal behavior is
treated in the next subsection.
Several factors should be considered to rationalize the
colloidal behavior of NPs having bare silica surfaces in
complex media. As discussed before, the dissociation of
silanols provides silica surfaces with a negative charge and,
consequently, with an ES repulsion that operates as a source
of colloidal stability. In this regard, the relatively high ionic
strength presented in media like PBS, SBF, or cell culture
Fig. 5 aPossible mechanisms involved in the surface stabilization of
silica nanoparticles accounting for their “anomalous”colloidal beha-
vior. bRepresentation of the most used strategies applied for enhan-
cing the colloidal stability of silica-based NPs. At the bottom of the
figure, the typical positive or negative groups used in the zwitterionic
strategies can be found
Journal of Sol-Gel Science and Technology

Table 2 Summary of selected works assessing colloidal stability of silica nanoparticles in biologically relevant fluids
Nanoparticles Coating Fluids Techniques Observations Ref.
MSN (50 nm) Bare, PEG SBF TEM / DLS PEGylated NP more stable than bare ones [40]
MSN (80 nm) Bare, PEG PBS DLS PEGylated NPs colloidally stable [117]
MSN (40–60 nm) Bare, PEG, PEG +hydrophobic silane (HS) PBS, DMEM (FBS 10%), SBF DLS Colloidal stability roughly ranks as NP-PEG +HS > NP-PEG bare >
bare NP
NP-PEG and NP-PEG +HS stable for days in different media
[104]
MSN (500 nm)
Non-porous 50 and 500 nm) Bare RPMI and RPMI +FBS 10% DLS / ζ-potential Colloidal stability roughly ranks as large non-porous NP > small non-porous
NP > MSN [93]
Non-porous (fluorescent; 30 and
80 nm) Bare PBS, DMEM, and Ham F-12 (with and
without FBS 10%) DLS / DCS / TEM NPs colloidally stable in FBS-free media
Smaller NPs less stable than Larger NP in FBS supp. Media [92]
Non-porous (50 nm) Bare MEM with FBS 10% DLS Gradual increase of NP size. Stable dispersion up to 300min [89]
Non-porous (50 and 200 nm) Bare Human plasma in PBS (0-80%) DLS / DCS Protein adsorption promotes NP colloidal Stability [99]
Non-porous (fluorescent 100 nm) Bare Human serum (0-100%) in PBS DCS NPs colloidally stable above 10% of human serum [100]
Non-porous (50 nm) Bare, Amine, Amino acids, PEG PBS, TRIS, DMEM, RPMI (with or without
FBS 10%) DLS / ζ-potential Colloidal stability roughly ranks as NP-PEG > bare > amines [37]
Non-porous (fluorescent 58 nm) Bare, Amine-Sulfonate mixtures BSA solution, DMEM (with and without
FBS 10%) DLS Amine:sulfonate 50:50 mixture shows the worst colloidal stability [138]
Non-porous (100 nm) Bare, Amine, Phosphonate (Ph.), Amine +Ph,
SBS, PEG PBS, DMEM and RPMI (with and without
FBS 10%) DLS / DCS All NPs stable in PBS
NP-Amine +pH. not stable in FBS supp. DMEM or RPMI [140]
Non-porous (100 nm) Bare, Amine, Thiol, PVP PBS, DMEM and DMEM +FBS 10% DLS / TEM Colloidal stability roughly ranks as NP-PVP > bare NP> NP-thiol > NP-
Thiol [90]
Non-porous (20, 30, and 100 nm) Bare, Carboxilic acid Buffer A, DMEM and DMEM +FBS 10% DLS NPs are colloidally instable in DMEM +FBS 10% [91]
Non-porous (20 nm) Bare, Cysteine (Cys) BSA, lysozyme and human serum
(25%) in PBS DLS / Turbidimetry NP-Cys more colloidally stable than bare NP [26]
Non-porous (10–220 nm) Bare, PEG BSA solution in PBS DLS / ζ-potential / TEM PEGylated NP more stable than bare NP
Explores influence of incubation time, concentration, and curvature among
other topics
[97]
Non-porous (110 nm) Bare, PEG PBS AFFF Colloidal stability and dispersibility of NP-PEG > bare NP [113]
Non-porous (40 nm) Bare, PEG, Sulfobetaine (SBS) Lysozyme and FBS PBS solutions
NaCl 0.5 and 3 M DLS / Turbidimetry NP-SBS and NP-PEG stable in protein solutions
NP-SBS tolerates high salt concentration (3 M) [43,128]
Non-porous (100 nm) Bare, PEG, SBS Lysozyme and BSA in PB (different
NaCl conc.) DLS / ζ-potential / ITC NP-SBS and NP-PEG stable in protein solutions (bare only in BSA solution)
NP-SBS aggregates in lysozyme solution at a low salt concentration [98]
Non-porous (120–140 nm) Bare, PEI-PEG PBS TEM / DLS NP-PEI-PEG colloidally stable [114]
Non-porous (60–120 nm) PBSMA Lysozyme and BSA in PBS DLS Polyzwitterion promotes colloidal stability [182]
Non-porous (60–220 nm) p-CBMA BSA and lysozyme in PBS DLS Coated NPs more colloidally stable than Bare NPs [146]
Non-porous (50–80 nm) p-DMAEMA-co-CBMA (different
quaternization degrees, QD) BSA in PB lysozyme in CHES DLS / Turbidimetry Colloidal stability improves with increasing QD [145]
Non-porous (50–500 nm)
MSN (500 nm) Bare RPMI and RPMI +FBS 10% DLS / ζ-potential Colloidal stability roughly ranks as large non-porous NP > small non-porous
NP > MSN [93]
MSN (50 nm) Bare, PEG SBF TEM / DLS PEGylated NP more stable than bare ones [40]
MSN (80 nm) Bare, PEG PBS DLS PEGylated NPs colloidally stable [117]
MSN (40–60 nm) Bare, PEG, PEG +hydrophobic silane (HS) PBS, DMEM (FBS 10%), SBF DLS Colloidal stability roughly ranks as NP-PEG +HS > NP-PEG bare >
Bare NP
NP-PEG and NP-PEG +HS stable for days in different media
[104]
Nanoparticles and coatings: MSN mesoporous nanoparticles, PVP poly(vinylpyrrolidone), PEG poly(ethyleneglycol), p-CBMA poly(carboxybetaine), PEI poly(ethyleneimine), PBSMA poly
(sulfobetaine methacrylate), DMAEMA 2-(dimethylamino)ethyl methacrylate, CBMA carboxybetaine methacrylate
Media: PB phosphate buffer, PBS phosphate buffer saline, MEM minimum essential medium, FBS fetal bovine serum, SBF simulated body fluid, DMEM Dulbecco’s Modified Eagle Medium,
RPMI Rose Park Memorial Institute medium, CHES N-Cyclohexyl-2-aminoethanesulfonic acid buffer, MEM minimum essential medium
Techniques: DLS dynamic light scattering, DCS differential centrifugal sedimentation, TEM transmission electron microscopy, AFFF asymmetric field flow fractionation
Journal of Sol-Gel Science and Technology

media (DMEM, RPMI) or biological fluids like plasma,
screens this ES repulsion, thus decreasing colloidal stability
[35,37]. On the other hand, adsorption of biomolecules, in
particular proteins, from complete cell culture media (sup-
plemented with FBS), diluted mammal’s plasma/sera, or
even single protein buffered solutions alters NPs’colloidal
behavior considerably. Protein adsorption onto silica NPs
usually decreases the NP ζ-potential, which tends to reach
the isolated protein (or proteome) ζ-potential value at
saturation, hence compromising colloidal stability
[91,93,97]. However, protein adsorption can be beneficial
for preventing NP aggregation owing to steric hindrance
depending on protein nature [35,97,99]. For this latter to
happen, it seems to be essential that a homogeneous protein
coating is formed over the NP. Otherwise, if the adsorbed
proteins are not uniformly distributed over the NP surface
(i.e., forming patches), bridging interaction may arise and,
combined with the already mentioned decrease in NP ζ-
potential, can promote aggregation [35,67,97]. Further-
more, the temporal evolution of the PC composition, when
NPs are dispersed in complex media containing several
different proteins (Vroman’s effect) [106–108], implies that
NP surface properties also evolve with time accordingly.
Then, the colloidal properties of the NPs might evidence
changes during the incubation time [36,49,100].
2.3 Surface modification as a strategy to enhance
silica nanoparticles colloidal stability
Silica NP surface functionalization is used to anchor tar-
geting moieties and biomolecules, prevent fouling and
aggregation, and regulate degradation, among other pur-
poses [8,109,110]. Every surface modification, regardless
of its ultimate goal, impacts NPs’colloidal stability. For
instance, silica NPs functionalization with amine groups,
using 3-aminopropyl(triethoxy)silane (APTES) or 3-ami-
nopropyl(trimethoxy)silane (APTMS), is frequently used as
afirst step for conjugating biomolecules in “grafting from”
approaches [109]. However, functionalization with APTES
or APTMS usually triggers silica NPs aggregation due to
positive surface charges (-NH3+) that counterbalance the
negative charges of pristine silica (≡Si-O−), and reduces the
absolute value of NP ζ-potential and ES repulsion [37].
Alternatively, Bagwe et al. proposed one of the first stra-
tegies for stabilizing amino-containing silica NPs through
simultaneous NP functionalization using APTES and 3-
(trihydroxysilyl)-propylmethylphosphonate [111].
Surface modification using PEG (see Fig. 5b) is perhaps
the most traditional strategy to maintain NPs colloidal sta-
bility on biological fluids [112] and has been widely applied
to different silica-based nanomaterials such as non-porous
[43,98,113–115], mesoporous [40,116], hollow-
mesoporous [117] and silica-coated NPs [118,119]. PEG
chains are strongly hydrated due to their hydrophilic nature
derived from the formation of hydrogen bonds between
water and PEG ether groups [120,121]. At appropriate
grafting densities, a layer of PEG provides steric repulsive
forces that prevent fouling (e.g., protein adsorption) and
aggregation in complex media [66,122]. Despite the
widespread use of PEGylation, PEG coatings present some
drawbacks like not preserving NP colloidal stability at high
ionic strengths and experiencing oxidative degradation in
environments containing transition metals and oxygen
[43,120,123].
Besides PEG, other neutral and hydrophilic polymers
have been used to functionalize NPs exposedsilica surfaces
to prevent aggregation. For instance, surface modification
with hyperbranched polyglycerol [124] and copolymer-
containing poly(N-isopropylacrylamide) (PNIPAM) [125]
have proven to improve the colloidal stability of silica-
coated NPs (gold, iron oxide, and quantum dots) and Stöber
silica NPs, respectively. In the latter case, the colloidal
stability also depends on temperature due to the thermo-
responsiveness of PNIPAM [126].
On the other hand, surface functionalization based on
zwitterions (neutral compounds having formal electrical
charges of opposite sign) [127] has gained attention in the
last few years as a powerful strategy for preventing fouling
and aggregation of NPs in biological media [121,122,128].
The use of zwitterions, mainly for antifouling purposes, was
inspired by the exposed headgroups of mammalian cell
membranes (composed primarily by phosphatidylcholine
zwitterionic molecule) that were demonstrated to prevent
biofouling on surfaces decorated with polymers [129–131].
Zwitterions electrostatically bind and structure water
molecules more efficiently than PEG and other hydrophilic
polymers. Hence, a NP surface coated with these com-
pounds must overcome a high dehydration energy barrier
for interacting with other nanometric objects nearby (e.g.,
other NPs, proteins) [41]. Moreover, the binding of mac-
romolecules containing distributed charges on their sur-
faces, like proteins, is relatively hindered for surfaces
exhibiting simultaneously negative and positive charges.
Small zwitterionic moieties (see Fig. 5b), such as sulfo-
betaine [43,98,128,132–134], carboxybetaine [135,136],
and phosphorylcholine, have been extensively employed to
maintain the colloidal stability of silica-based nanomater-
ials. Moreover, amino acids like cysteine or arginine have
also been used to produce zwitterionic coatings that effec-
tively avoid silica NPs aggregation in complex media
[26,137]. Alternatively, the NP surface can be simulta-
neously tailored with moieties bearing positive (e.g.,NH
3+,
-NH(CH3)2+) and negative (e.g.,SO
3
−, -PO3
−, -PCH3O2
−)
groups and give rise to “pseudo-zwitterionic”surfaces that
result in good colloidal stabilization [138–140]. In this case,
the ratio between positive and negative moieties must be
Journal of Sol-Gel Science and Technology

carefully engineered to optimize surface passivation against
aggregation and protein adsorption.
Polymeric zwitterions (see Fig. 5b) containing pendant
sulfobetaines [141–143], carboxybetaine [144–146], or
phosphorylcholine [147,148], among others moieties [149],
have also been applied for coating and preserving silica NPs
colloidal stability in biological environments. In addition to
the already mentioned mechanisms accounting for small
zwitterions’significant influence on NP interactions and
colloidal stability, polymeric zwitterions also take advan-
tage of the steric effects related to their larger volume [122].
It is also worth mentioning that NPs purification proce-
dure and storage (liquid suspension vs.dry powder) before
the transference to the testing media can profoundly influ-
ence the colloidal behavior. In particular, silica NP dried
powders are difficult to redisperse due to the formation of
interparticle siloxane bonds that result in irreversible
aggregates [150,151]. In this case, any further evaluation of
the NP colloidal behavior will be heavily biased by this
original aggregation. For instance, this situation is fre-
quently observed in MSNs produced following procedures
implying calcination for organic template removal or
pyrogenic non-porous silica NPs, but not restricted to these
examples [104]. Despite this, silica NP powders with good
redispersability in relevant media and showing reduced to
negligible aggregation attributed to the dry state can be
produced by freeze-drying in the presence of proper pro-
tectants such as simple carbohydrates [151] or albumin
[22,50].
3 Degradation of silica nanoparticles in vitro
and in vivo
3.1 Basics on silica nanoparticles degradation
The complete silica-based nanomedicines clearance from
the body after their therapeutic and diagnostic effects must
be guaranteed before their translation from bench to clinics
[2,152]. Some silica materials have been considered safe by
the FDA, mainly due to the low toxicity of silicic acid (the
main product of silica degradation) and the presence of
silicates on several body tissues [27]. However, it has been
reported that silica NPs can accumulate in organs such as
the liver and spleen after administration leading to silicosis
[20,27]. Thus, tuning silica NPs degradation is of utmost
importance since this process can improve the excretion of
ultrasmall silica fragments by the urinary and intestinal tract
[20,27].
Silica surface is naturally prone to nucleophilic attack in
aqueous solutions, causing the erosion of their external
structure and inducing premature damage, which can be
favored or hampered depending on the groups disposed onto
its surface [105,153]. On the other hand, the degradation of
silica can be regulated by doping its structure using
degradable sites, such as di- and tetrasulfide species, Schiff
base, oxamide-phenylene groups, and metallic ions [3,154–
157]. These sites can undergo degradation when triggered by
a specific stimulus, such as pH [154], enzymatic attack
[155], and redox reactions [3].
In aqueous media, the dissolution of silica framework
results from sequential surface hydration and hydrolysis
(see Fig. 6a). After water molecules adsorb onto siloxane
(Si-O-Si) and silanol (Si-OH) species, an electropositive
silicon atom is attacked by a hydroxyl group (OH-) from the
medium, resulting in an unstable pentavalent intermediate
complex. Then, this structure is further attacked by another
hydroxyl group, opening the silica structure by converting a
siloxane into a silanol group [20]. As a consequence, silicic
acid (Si(OH)4) is released. Fortunately, silicic acid and other
polysilicic acids (which are also found after hydrolysis of
silica surfaces) [158] are nontoxic [159], able to diffuse
through blood and lymphatic vessels and, eventually, are
eliminated in the urine [160]. The degradation kinetics of
silica surfaces has been modeled through Eq. 1, taking into
account the surface concentration of three silanol species:
protonated (Si-OH2+), neutral (Si-OH), and deprotonated
(Si-O-)[28].
Rdiss ¼kHþ
ðÞ
SiOHþ
2

mþkH2OðÞ
SiOH½þkOH
ðÞ
SiO
½
p
ð1Þ
In the equation, Rdiss is the rate of dissolution, [Si-OH2+],
[Si-OH], [Si-O−] are the surface concentration of the three
mentioned species, k(H+),k(H2O), and k(OH−)refer to dis-
solution rate constants, and mand pstand for reaction
orders.
The degradation rate of silica NPs strongly depends on
the characteristics of both the media (pH and composition)
and the NPs (composition, porosity, colloidal stability, and
condensation rate) [27]. The pH effect on silica dissolution
has been widely reported in the last few decades to under-
stand the chemical stability, catalytic, and adsorption
activity of silica-based materials in different aqueous solu-
tions [161–163]. It defines the concentration of protonated
and deprotonated species onto silica’s surface and, hence,
deeply impacts the silica degradation rate. Ideally, the IEP
of bare colloidal silica ranges from pH 2–4 in water, and the
concentrations of protonated and deprotonated are more
prominent in pH < 1 and pH > 5, respectively. Thus, the
hydrolysis and degradation of the silica surface would be
more likely to happen in pH conditions below or above
silica’s IEP, since the energy barrier for this process in both
protonated and deprotonated sites is lower [164,165].
However, in a more complex scenario, the silica NPs’IEP is
Journal of Sol-Gel Science and Technology

shifted toward the IEP of the adsorbed species, which can
be “impurities”from the medium (e.g., ions and proteins) or
functional groups attached to the particle surface, changing
the pH in which the degradation of its structure would occur
[61,64]. Therefore, the IEP’s determination under these
conditions would be a challenge once the high concentra-
tion of ionic groups and their interactions, for instance, can
lead to experimental errors, such as imprecision in the pH
measurement [166,167].
3.2 Influence of media on the degradation of silica
nanoparticles
In the last few years, the increasing interest in silica NPs in
nanomedicine has propelled studies about their degradation
behavior in SBF under different pHs and compositions (a
compilation of studies is found in Table 3)[20,27]. For
instance, it has been demonstrated that silica-based NPs
with different structural features present higher degradation
rates in simulated lysosomal fluids (pH 4.5), simulated
intestinal fluids (pH 6.5), and SBF (pH 7.4) than in simu-
lated gastric one (pH 1.2) [20].
Mono- and bivalent ions, organic salts, amino acids, and
proteins are examples of components in biological envir-
onments that can influence silica NPs degradation [168].
Table 1summarizes the most popular different media
compositions used along with the degradation studies.
These media can potentially enhance silica degradation due
to their ionic rich content since the adsorption of cations
onto silica surface can weaken the siloxane bonds (Fig. 6b),
while anion adsorption can enhance silanol deprotonation. It
stimulates siloxane hydrolysis and further silica fragments
leaching from the particle surface [20,51]. As reported
previously, simulated lung fluids (SLF) and SBF promote a
higher degradation of MSNs than simulated gastric fluid
(Table 3)[51]. This result reflects the impact of differences
in the composition and pH of the used media (Table 1).
Salts of organic acids and proteins, which are particularly
important in complex physiologic fluids, have significantly
impacted silica degradation. Organic acid salts, mainly di-
and tri-carboxylates, have been described as the main factor
of the higher silica degradation rates observed in SLF
[28,51]. This behavior has been attributed to the formation
of complexes between carboxylates and silica surface by
nucleophilic attack of the former toward electropositive
silicon atoms of the latter. Alternatively, the nucleophilic
attack of the carboxylic acid from proteins to silicon atoms
is facilitated by the interaction of aminated protein moieties
with the Si-O−groups on silica surfaces (Fig. 6b) [28]. For
instance, MSNs degradation enhancement has been reported
in DMEM supplemented with FBS (10%). Signs of degra-
dation have been detected for 87 nm MSNs after 2 h of
incubation and, after 60 days, 54% of MSNs had been
degraded in FBS-enriched DMEM. Conversely, no sig-
nificant degradation has been observed in FBS-free DMEM
[38]. Complementary, silica-based NP degradation tests in
the intracellular environment have shown, after 72 h of
incubation, that only ~3.8 and ~0.3% of MSN (100 nm) and
Fig. 6 Schematic representation of the silica degradation mechanisms in awater (at IEP) and bin biological media, considering the influence of
different factors—surface functionalization and adsorption of ion and proteins
Journal of Sol-Gel Science and Technology

non-porous silica NP (100 nm) structures degraded,
respectively [20]. The degradation mechanism in intracel-
lular environments and throughout the in vivo tests is still to
be revealed. The results and conditions of degradation
experiments reported in several studies in vitro and in vivo
are presented in Tables 4and 5.
3.3 Influence of silica nanoparticles structure on
their degradation
Silica NPs structural characteristics are as important as the
media along their degradation process [2,27,169]. For
instance, while non-porous particles do not significantly
degrade in different media compositions, porous particles
are highly susceptible to environmental conditions [38].
Porous particles allow better diffusion of the medium
through its structure and, hence, provide enhanced interac-
tion of silanol and siloxane groups with ions, proteins, and
other media [105,170]. Studies have shown that particles
with larger pore sizes degrade faster than the ones with
smaller pores and similar surface area [171,172]. Alongside
porosity, the condensation degree also plays a significant
role in silica NPs degradation rate [27,105,171]. A highly
condensed silica particle, which is usually obtained by the
sintering process, presents a majority of Q4sites ((SiO)4-Si)
and a minority of Q3species ((SiO)3-Si-OH) [27,51,105].
Conversely, non-calcined silica NPs show higher Q3con-
tents while the overall Q4amount is minor. The porosity
also impacts on silica NPs condensation degree, for
instance, MSNs present a lower condensation degree (Q4/Q3
Table 3 Degradation conditions and outcomes of silica-based nanoparticles in biological fluids
Nanoparticles Doping or/and coating Fluids Techniques Tested time Observations Ref.
HSN Disulfide doping PBS +GSH TEM 48 h Full degradation (48 h) [183]
MSN PEG coating
-Cl coating
-NH2coating
SBF BET / TEM 28 d PEG—partial degradation (28 d)
Cl—full degradation (28 d)
NH2—full degradation (28 d)
[105]
MSN –SGF/SIF/SBF +GSH ICP-MS /
TEM
28 d SGF—6% degraded (28 d)
SIF—100% degraded (28 d)
SBF—100% degraded (6 h)
[20]
MSN Disulfide doping SGF/SIF/SBF +GSH ICP-MS /
TEM
28 d SGF—19% degraded (28 d)
SIF—55% degraded (28 d)
SBF—13% degraded (6 h)
[20]
MSN –SLF/SBF/SGF/PBS ICP-MS 8 h SLF—full degradation (6 h)
SBF—full degradation (6 h)
SGF—partial degradation (14 d)
PBS—full degradation (6 h)
[51]
MSN –SBF TEM 96 h Full degradation (24 h) [171]
MSN PEG and FA coating PBS +GSH ICP-OES /
TEM
72 h pH 5—90% degraded (14 d)
pH 7.4—15% degraded (14 d)
[184]
MSN Lysine-silane doping DI Water +trypsin TEM 72 h Full degradation (72 h) [185]
Organosilica Oxamide-phenylene doping PBS +trypsin TEM 48 h Partial degradation (24 h)
Full degradation (48 h)
[155]
Organosilica Ethylene doping PBS +ME TEM / DLS 48 h Full degradation (48 h) [186]
Organosilica Oxamidedoping PBS +trypsin TEM / FTIR 48 h Full degradation (48 h) [187]
Organosilica Disulfidedoping PBS +ME TEM 48 h Full degradation (48 h) [188]
Stöber –SGF/SIF/SBF ICP-MS /
TEM
28 d SGF—8% degraded (28 d)
SIF—46% degraded (28 d)
SBF—64% degraded (28 d)
[20]
Stöber –SLF/SBF/SGF/PBS ICP-MS 8 h SLF—full degradation (8 d)
SBF—full degradation (10 d)
SGF—no degradation (14 d)
PBS—full degradation (14 d)
[51]
Stöber Disulfide doping PBS +GSH TEM 5 d Full degradation (5 d) [189]
Mn-MSN Mn doping PBS +GSH ICP-MS /
TEM
15 d Full degradation (15 d) [190]
Mn-MSN Mn doping SBF +GSH ICP-OES 12 h Full degradation (12 h) [191]
Zr-MSN Zr doping PBS TEM 24 h Slight degradation (24 h) [192]
ME mercaptoethanol, DI distilled, FA folic acid, GSH gluthatione
Journal of Sol-Gel Science and Technology

around 2–2.5) compared to Stöber non-porous particles (Q4/
Q3around 5–10). Accordingly, only 30% of a calcined and
non-porous silica NP degrade after 15 days, while a non-
calcined MSN can fully degrade in less than 48 h [27].
3.4 Strategies to tune silica nanoparticle
degradation
The silica NPs degradation rate is highly dependent on how
extensively the media can access the silica surface
[105,170]. Then, good colloidal stability allows proper
interaction between media and individual particles, resulting
in faster particle degradation [27,172]. In contrast, the
media components’access to the inner region of aggregated
particles is limited and leads to lower degradation rates
[172]. As aforementioned, silica NPs functionalization can
prevent particles aggregation, improve colloidal stability
and enhance surface exposure. However, depending on the
surface modification, this approach can also delay the par-
ticles degradation process[105,153]. The functionalization
of porous silica NPs with -phenyl, -NH2, and -Cl groups has
been demonstrated to lead to fast degradation of the particle
(<24 h), which is attributed to the low condensation degree
of the silica structure and insufficient protection provided by
these groups (Table 4). In contrast, when PEG coats silica
NPs, the sample has shown enhanced structural stability in
biologically relevant media and presented signs of degra-
dation only after 4 days of incubation in SBF [105]. In
addition, several studies have shown that the degradation
behavior of MSNs is modified after their surface functio-
nalization. While non-functionalized mesoporous particles
are degraded by a combination of surface erosion and pore
degradation [105,173–175], particles functionalized with
polymers start degrading from the interior of the pores (see
Fig. 7)[38,169,176].
In the nanomedicine scenario, silica NPs degradation
before reaching the target is undesirable since premature
drug leakage leads to efficiency loss. Unfortunately, pure
silica NPs degradation cannot be designed to be triggered
by any given condition [152]. For this reason, scientists
were driven to introduce responsive sites into the silica
framework to control the degradation rate of silica-based
NPs (Fig. 8)[27]. These sites are usually composed of
organic moieties that respond to a specific exterior stimulus
and, when triggered, lead to NP structure fragmentation
[2,27,152]. Then, a wide range of organosilane groups has
been used to trigger silica NPs degradation under specific
conditions. Precursors containing di- and tetrasulfide, amino
Table 5 Degradation conditions
and outcomes of silica-based
nanoparticles in ex vivo and
in vivo
Nanoparticles Doping or/and
functionalization
Particle
concentration
Tested time Observations Ref.
MSN –10–200 mg/kg 10 d Full excretion (4 d) [196]
89Zr-MSN 89Zr labeling 100 uL of 1 mg/mL 48 h Partial excretion
(48 h)
[197]
MSN –25 mg/kg 7 d 53% excreted (7 d) [20]
MSN disulfide doping 25 mg/kg 7 d 39% excreted (7 d) [20]
MSN –20 mg/kg 4 d Full excretion (4 d) [198]
Stöber –25 mg/kg 7 d 27% excreted (7 d) [20]
Table 4 Degradation conditions and outcomes of silica-based nanoparticles in cell culture media and intracellular environment
Nanoparticles Doping or/and coating Culture media/cell line Technique Tested time Observations Ref.
MSN –Lonza Mesenchymal Stem Cell
Growth Medium
TEM/ICP 21 d Full degradation (18 d) [193]
MSN Containing AuNPs IMDM or RPMI +FBS TEM 72 h Full degradation (4 h) [194]
MSN –IMDM or RPMI +FBS TEM 72 h No degradation (72 h) [194]
MSN PEG and FA coating HepG2 cells TEM 72 h Full degradation (72 h) [184]
MSN –DMEM TEM 60 d No degradation (60 d) [38]
MSN –DMEM +FBS TEM 60 d Partial degradation
(60 d)
[38]
Organosilica Disulfide doping DMEM +FBS TEM 48 h Full degradation (48 h) [195]
Organosilica Disulfide doping RAW 264.7 macrophages ICP-MS 72 h Slight degradation
(72 h)
[20]
Stöber –RAW 264.7 macrophages ICP-MS 72 h Slight degradation
(72 h)
[20]
Journal of Sol-Gel Science and Technology

acids, and Schiff base can be degraded by redox reactions,
enzymatic attacks, and pH variations, respectively. Thus,
silica NPs containing redox responsive groups, for example,
can be triggered by reduced glutathione (GSH) in the cell
cytosol, making these engineered systems a promising
alternative to promote drug release into targeted cells
[3,20]. Therefore, the combination of surface functionali-
zation (using polymers or zwitterionic groups) and
responsive organosilanes is a promising strategy to suc-
cessfully control silica-based NPs while guaranteeing the
NP degradation in a pre-defined environment.
Even though organosilane groups on silica NPs struc-
tures can be employed to tune their controlled degradation,
several studies report that their use delays the complete
clearance from the body [20,177]. This phenomenon is
likely explained through the hydrophobicity induced by the
organosilanes structure after the NP collapse and hinders
further degradation of the silica moiety to small fragments
(<5 nm). This trend was reported in the literature, where
only 1.2% of the structure of MSNs containing disulfide
organosilane was degraded after 72 h in an intracellular
environment, while its pure silica counterpart degraded
3.8% in the same period [20]. Conversely, the same study
showed that silica fragments concentration (<5.5 nm) in
mice kidneys was higher for MSN containing disulfide
Fig. 8 Timeline of the complete degradation in aqueous media of different silica nanoparticles based on their porosity and composition. This figure
was adapted from Croissant et al. [27] and reproduced with permission from Wiley
Fig. 7 Schematic representation of the degradation course, in biolo-
gical media, of mesoporous (top), functionalized mesoporous (middle),
and non-porous (bottom) silica nanoparticles
Journal of Sol-Gel Science and Technology

groups (ca. 26%) than the amount detected for pure silica
MSN and non-porous silica NP, which was around 10%
[20]. This disparity clearly indicates the relevant impact of
biological mechanisms on silica-based NP degradation and,
yet, this process remains unclear.
In an attempt to enhance silica-based NP biocompatibility,
researchers have been also doping silica NPs with metal or
metal oxides to either accelerate (iron, manganese, and cal-
cium) or delay (zirconia and aluminum) silica NPs degrada-
tion. The advantages of silica doping with iron, calcium, and
manganeseincludeafasterNPsclearanceduetothewide
range of interactions of these ions with biological species
promotinganefficient degradation. In addition, several studies
have shown that these particles can also be responsive to
media stimuli. For instance, Mn-doped MSNs are triggered by
mild acidic and reducing environments [156,178,179], fol-
lowed by Ca-doped MSN that also degrades under acidic
conditions [157]. Conversely, in zirconia and aluminum-
dopped systems, the degradation rate is lagged due to the
higher chemical stability of the framework [27]. Some
examples of degradation conditions and outcomes for dopped
silica NP are also presented in Tables 3–5.
4 Conclusions and perspectives
Efforts have been made to understand the bio-related aggre-
gation and degradability of silica NPs in biological fluids.
Consequently, this knowledge has built up evidence of the
role of different parameters in this complex puzzle. Silica NPs
morphology, porosity, and density have an evident impact on
their colloidal stability and degradation rates, which are
usually enhanced by environmental features (composition,
pH, and ionic strength). Silica NPs surface functionalization
with protectant agents has successfully prevented these
undesirable processes in SBF and cell culture media. Never-
theless, the reported studies are still performed in highly
controlled media conditions, where the NP concentration is
pre-defined, and the environment composition is well known.
Thus, the direct translation of these systems to medical
treatments is not trivial. These studies are limited to experi-
mental conditions far from grasping the real response when
applied in vivo. Therefore, further advances in this field still
rely on the comprehension of silica NPs behavior in whole
blood and living tissues. Then, it is imperative to correctly
answer how silica NPs engage with each major blood com-
ponent, what path is followed after cell uptake, and how they
achieve complete clearance from the body. The advances
made in the last decade represent a solid ground to boost the
following steps, but we still have a long path ahead. We
envisage that breakthrough understanding of the silica NPs
behavior in the biological environment will be only possible
when high-resolution techniques (such as synchrotron and
electron microscopy techniques) are fully designed and opti-
mized to probe colloidal stability in complex media, NP-cell
interaction, and NP degradation.
Acknowledgements The authors also acknowledge the financial sup-
port of the Fundação de Amparo à Pesquisa do Estado de São Paulo
(processes 2018/00763-8, 2019/24894-7, 2016/16905-0, 2020/00767-
3, and 2015/25406-5). ASP and MBC acknowledge UNLP and
CONICET for their support. ASP and MC staff members of CONICET.
Compliance with ethical standards
Conflict of interest The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
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