Review

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Nanoarchitectured Structure and Surface Biofunctionality

of Mesoporous Silica Nanoparticles
Ranjith Kumar Kankala, Ya-Hui Han, Jongbeom Na, Chia-Hung Lee, Ziqi Sun, Shi-Bin Wang,
Tatsuo Kimura, Yong Sik Ok, Yusuke Yamauchi,* Ai-Zheng Chen,* and Kevin C.-W. Wu*
This article is dedicated to Dr. Victor S.-Y. Lin, who was a professor of chemistry at Iowa State University
from 1999 until he unexpectedly passed away in 2010. Victor was a pioneer in the synthesis and applications
of mesoporous silica nanoparticles (MSNs), a term he created to describe nanometer-sized mesoporous
silica materials with well-defined and controllable properties in the biomedical and catalytic applications.

1. Introduction
Mesoporous silica nanoparticles (MSNs), one of the important porous mate-
rials, have garnered interest owing to their highly attractive physicochemical Since ever the nanotechnology revolu-
tion has begun in the mid-1950s; indeed,
features and advantageous morphological attributes. They are of particular
the rapid progress in nanotechnology has
importance for use in diverse fields including, but not limited to, adsorption, evidenced the generation of diverse nano-
catalysis, and medicine. Despite their intrinsic stable siliceous frameworks, materials/nanostructures (1–100  nm in
excellent mechanical strength, and optimal morphological attributes, pris- one or more dimensions) with inherent
tine MSNs suffer from poor drug loading efficiency, as well as compatibility functionalities, owing to their exceptional
and degradability issues for therapeutic, diagnostic, and tissue engineering benefits, such as convenient synthesis and
scalability, as well as tailorable morphology
purposes. Collectively, the desirable and beneficial properties of MSNs have
(size/shape)-dependent physicochemical
been harnessed by modifying the surface of the siliceous frameworks through features.[1–2] The attractive features of
incorporating supramolecular assemblies and various metal species, and these nanostructured components could
through incorporating supramolecular assemblies and various metal species be present either in the final or interme-
and their conjugates. Substantial advancements of these innovative col- diate forms of the intended constructs and
have enabled them to find their ways in
loidal inorganic nanocontainers drive researchers in promoting them toward
various fields, such as agriculture, engi-
innovative applications like stimuli (light/ultrasound/magnetic)-responsive neering, energy production, and medicine,
delivery-associated therapies with exceptional performance in vivo. Here, a among others. The supreme importance
brief overview of the fabrication of siliceous frameworks, along with discus- gained for utilizing such innovative
sions on the significant advances in engineering of MSNs, is provided. The nanomaterials is due to their nature of
scope of the advancement in terms of structural and physicochemical attrib- exhibiting two key intrinsic features, i.e.,
abundant surface chemistry for immobi-
utes and their effects on biomedical applications with a particular focus on
lizing various guest species and targeting
recent studies is emphasized. Finally, interesting perspectives are recapitu- ligands and high surface-to-volume ratio
lated, along with the scope toward clinical translation. for encapsulating diverse guest species,

Prof. R. K. Kankala, Dr. Y.-H. Han, Prof. S.-B. Wang, Prof. A.-Z. Chen Dr. J. Na, Prof. Y. Yamauchi
College of Chemical Engineering International Center for Materials Nanoarchitectonics (WPI-MANA)
Institute of Biomaterials and Tissue Engineering National Institute for Materials Science (NIMS)
Fujian Provincial Key Laboratory of Biochemical Technology 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan
Huaqiao University Prof. C.-H. Lee
Xiamen 361021, P. R. China Department of Life Science and Institute of Biotechnology
E-mail: azchen@hqu.edu.cn National Dong Hwa University
Dr. J. Na, Prof. Y. Yamauchi Hualien 97401, Taiwan
School of Chemical Engineering and Australian Institute for Prof. Z. Sun
Bioengineering and Nanotechnology (AIBN) Science and Engineering Faculty
University of Queensland Queensland University of Technology
Brisbane, QLD 4072, Australia 2 George St, Brisbane, QLD 4000, Australia
E-mail: y.yamauchi@uq.edu.au Dr. T. Kimura
The ORCID identification number(s) for the author(s) of this article National Institute of Advanced Industrial Science and Technology (AIST)
can be found under https://doi.org/10.1002/adma.201907035. Nagoya 463-8560, Japan

DOI: 10.1002/adma.201907035

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including small drug molecules, genes, and contrast agents.[3]

Besides, tremendous advancements in the recent past have been Yusuke Yamauchi received
evidenced by the steady growth of nanotechnology in different his Ph.D. degree (2007)
fields, which poised to have a significant impact in the future. from Waseda University
Among various inorganic-based nanomaterials, mesoporous (Japan). After that, he joined
silica nanoparticles (MSNs) have captivated vast attention of NIMS to start his research
researchers due to their highly beneficial morphological ­features group. In 2017, he moved to
such as extensive specific surface area and pore volume, tunable Australia to join the School
sizes and shapes, and ease of surface functionalization as well as of Chemical Engineering
attractive physicochemical properties, such as abundant surface and AIBN at The University
chemistry, colloidal stability, and high dispersity.[4–6] The excep- of Queensland as a full
tional topology with surface and inner porous architectures of professor and a senior group
the MSNs makes them exceptional with anticipated properties, leader, respectively. He spe-
which could be well-regulated by adjusting the synthesis condi- cializes in the design of functional nanospaces in inorganic
tions.[7] Such desirable characteristics are of particular interest materials with controlled compositions and morphologies
in catalysis, polymeric fillers, adsorption, optical devices, and toward practical applications.
diverse applications in biomedicine, such as bioimaging, bio-
catalysts, biosensing, tissue engineering, as well as targeted and Ai-Zheng Chen received his
controlled drug/protein/gene delivery systems.[8–10] Ph.D. degree in biomedical
Mesoporous silica-based material was reported in the engineering from Sichuan
early 1990s for the first time by Mobil scientists, Kresge and University in 2007. After
co-workers, who named these hierarchical crystalline molecular completing postdoctoral
sieves, by combining the silica precursor with the surfactant research at The Hong Kong
molecules, ensuing in the formation of ordered mesoporous Polytechnic University, he
materials.[11] Parallel attempts from Yanagisawa et  al., who joined Huaqiao University,
fabricated 3D silica networks involving the generation of alkyl where he is now a professor
trimethylammonium-kanemite complexes, are highly acknowl- at the College of Chemical
edgeable.[12] Depending on the type of surfactant template used, Engineering and Director
MSNs can be broadly classified into three predominant categories of Institute of Biomaterials
based on the type of surfactant, such as cationic (cetyltrimeth- and Tissue Engineering. He was a visiting research
ylammonium chloride, CTAC, and cetyltrimethylammonium professor for one year in Prof. Ali Khademhosseini’s
bromide, CTAB), anionic (phosphoric acid, N-myristoyl-l-ala- Laboratory at Harvard Medical School. His research
nine, sodium dodecyl sulfate, sulfonic acid, and alkyl ­carboxylic interests include drug delivery systems and tissue
acids), and nonionic (block copolymers based on polyethylene engineering.
oxide (PEO) and polypropylene oxide (PPO), Pluronic F123, as
well as F127, and Brij 30) surfactants. These templates result Kevin C.-W. Wu received
in various ordered mesostructured architectures: M41-series, his Ph.D. degree from The
Mobil Composition of Matter (MCM)-41 (2D hexagonal, p6mm), University of Tokyo in 2005.
MCM-48 (3D cubic, Ia3d), and MCM-50 (lamellar, p2); anionic After that, he was a post
surfactant-templated mesoporous silicas (AMS)-series; Santa doc at Iowa State University
Barbara Amorphous (SBA)-series; and Institute of Bioengi- with Prof. Victor Lin in USA
neering and Nanotechnology (IBN)-series; as well as Korean from 2005 to 2008, where
Institute of Science and Technology (KIT)-series, respec- he learned biomedical
tively.[13–16] Since their inception, diverse types of MSNs have applications of MSNs. He
gathered the phenomenal attention from researchers and have is currently a professor at
become as apparent promising delivery vehicles. the Department of Chemical
MSNs are known for their compatibility at appropriate Engineering, National Taiwan
doses due to their extensive silanol groups, which often result University (NTU), Taiwan. His main research interests are
the structural design and tailoring of functional nanopo-
Prof. Y. S. Ok
rous materials for sustainable chemistry and engineering
Korea Biochar Research Center applications including biomass conversion, biomedicine,
APRU Sustainable Waste Management & Division of Environmental and energy devices.
­Science and Ecological Engineering
Korea University
Seoul 02841, South Korea in nontoxic silicic acid species.[17] Owing to this fact, several
Prof. K. C.-W. Wu investigations in vitro have been performed and were encour-
Department of Chemical Engineering
National Taiwan University
aging. Despite the success in the assessments in vitro and
Taipei 10617, Taiwan their impeccable extrapolation toward in vivo, in some of the
E-mail: kevinwu@ntu.edu.tw aspects, such as compatibility, efficacy, and distribution, the in

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Figure 1.  Schematic illustrating the critical advances and specific attributes of engineered MSNs. Advances in MSNs by modifying the appropriate
structural attributes of stable siliceous constructs, i.e., surface, siliceous frameworks, and porous structures, and listed the augmented intrinsic as well
as the acquired physicochemical properties.

vivo assessments of MSNs, concerning the long-term circula- tuning the mesopores. In addition, various other advancements
tion, distribution, and overall fate of the nanoparticles, failed toward enriching these restructured frameworks result in the
to exhibit anticipated results due to the sophisticated physi- fabrication of hetero-nanostructures of dynamically modu-
ological environment with multiple biological barriers. Often, lated (deformable solids) and irregular-shaped (multipedal and
these ­shortcomings limited the utilization of MSNs as the Janus-type) architectures with high morphological and physico-
clinical translation of any formulation requires comprehensive chemical complexity, referring to advanced MSNs (Figure 1).[18–
preclinical investigations that are establishing the physiolog- 19]
Following that, we illustrate the advances in MSN properties
ical behaviors of MSNs, which are predominantly dependent with the progression in their fabrication. Finally, we recap the
on the synthesis procedure of MSNs.[7] However, in addition review with critical perspectives emphasizing the next chal-
to safe conveyance and biocompatibility in the biological envi- lenges to be addressed for their transformation from the bench
ronment, following the physiological standards, it should be to the bedside.
noted that some of the critical factors can alter the biobehav-
ioral characteristics of the MSNs, such as heterogeneity of
the tissue microenvironment, specifically in cancer therapy 2. Generalized Fabrication of MSNs
as different cancers vary in vascularization and lymphatic
drainage. With the beneficial physicochemical characteristics, In general, the highly ordered mesoporous silica species are
it is extremely desirable to harness the favorable and advan- synthesized based on the surfactant-templating approach,
tageous features of MSNs by various advancements for their which predominantly utilizes surfactant molecules (e.g., CTAB)
exploration in the ground-breaking applications with better as structure-directing templates and tetraethoxysilane (TEOS) as
performances. the silica source. Though the mechanism of MSN formation is
Although numerous reports based on MSN-based nano­ not convincing, it can be concluded through general principles
systems for biomedical applications have been emphasized by of particle formation. In a generalized mechanism of MSN for-
other groups and us, the scope of the review covers the critical mation, initially, the added surfactant molecules in the alkales-
advances of the MSNs over the past two decades, highlighting cent medium are self-assembled systematically in the form of
the recent investigations and facts exploring the clinical transla- micelles at their critical micelle concentration (CMC). Further,
tion of the advanced MSNs.[6–9,13] Further, we first discuss the the addition of silica results in the nucleation and subsequent
formation of MSN frameworks elucidating the effects behind growth by cocondensation through interactions that are driving
the mechanisms involving reaction kinetics and factors influ- the organic–inorganic components into the uniform-sized
encing their formation. We then discuss the modifications architectures (Figure  2A). Similarly, MSNs can also be synthe-
made in terms of scope of advancements are predominantly sized by employing a fast change in the pH value based on the
confined to three significant aspects, i.e., functionalizing hydro- prehydrolysis silica precursor, resulting in the rapid neutraliza-
philic surface, changing the patterns of silica frameworks, and tion (Figure  2B).[6] Indeed, it is highly required to understand

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Figure 2.  Schematic showing the assembly of substrates and interactions in various environments. A) Illustration showing the generalized formation
mechanism of MSNs cationic surfactant as a template. B) Fast self-assembling method for the preparation of MSNs by cationic surfactant as a template
using fast pH changing method. Reproduced with permission.[6] Copyright 2013, Royal Society of Chemistry.

the nucleation and subsequent crystal growth mechanisms to components and the silica condensation rate often affect both
effectively control the size as well as uniformity of the particles the nucleation and crystal growth rates. In some cases, apart
and their overall morphology of the mesostructures. In general, from base and silica, the addition of cosolvents also plays a
the formation of MSNs can be correlated to the classical growth vital role in the orientation of nanochannels during the crystal
mechanism of metal constructs such as metal nanoparticles growth of MSNs. In the case of mesoporous silicas based on
and their assemblies. Oftentimes, the creation of a burst of tiny nonionic surfactants such as SBA-15, it was presumed that
homogenous nuclei, act as templates, is thermodynamically the siliceous network could be constructed in the liquid crystal-
considered. Further, the continuous nucleation conjugated with line phases of the surfactants, resulting in the core–shell com-
the aggregation of primary particles leads to their subsequent posite structures and eventual separation of templates through
crystal growth into increased sizes, resulting in the uniform- calcination leads to MSNs.
sized particles. MSNs with diverse morphologies have been fabricated and
The precise control over the morphological attributes of systematically investigated by adjusting the synthetic condi-
MSNs can be governed by the kinetic effects of self-assembled tions, such as pH, surfactant templates as well as the silica
surfactant molecules and the subsequent nucleation based on source. The foremost significant aspect that influences the
resultant hydrolysis of silica source into silicate oligomers. formation of MSNs is the pH value of the synthesis solution,
Further, the growth process of the nuclei is guided by the con- at which the charge of the silica species affects the subse-
densation of the consequent oligomers, directing the particle quent hydrolysis and the condensation reaction rates.[21] The
morphology substantially. However, the nucleation, as well as silica species based on the isoelectric point (IEP) exhibit dif-
growth steps, should be considered separately as the multiple ference in charge, concerning the pH value of the synthesis
nucleation steps may lead to broad particle size distribution. solution, baring negative charge at a pH above the IEP, and
The structural control of MSNs can be attained by using the vice versa. However, it should be noted that the assembly of
block copolymer P123 through controlling the diffusion of such silicates with high charge densities at the alkaline conditions
silicate oligomers formed during the nucleation. The block is only conceivable with the cationic surfactants like CTAB,
copolymer surfactant at a temperature above its cloud point resulting in the arbitrary size range (10–100  nm).[17] In addi-
can convert the hydrophilic PEO part into the hydrophobic seg- tion to pH value, the selection of a suitable surfactant and its
ment, which prevents the interaction with the silica species and concentration also play significant roles in the fabrication of
limits the diffusion of silicate oligomers through the synthesis MSNs. In addition to cationic surfactants, the use of binary
gel.[20] Moreover, critical care should also be taken to prevent surfactants with differences in the molecular weight, including
the aggregation and for maintaining the stable suspension. the coblock polymers, such as polystyrene-b-poly(acrylic acid),
Owing to the complexity of involving multiple components (PS-b-PAA) along with CTAB as a cotemplate, may result in
such as surfactants and silica, the interactions between such the generation of highly tunable dual-mesoporous core–shell

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architectures that strictly driven by the surfactant assembly.[22] structures. Then, we discuss the changes in the porosity of
Moreover, the Pluronic triblock copolymer and other fluoro- the MSNs, i.e., cage-like and hollow structures, highlighting
carbon surfactants with a different hydrophobicity can also be the hollow-, yolk–shell-, and core–shell-based architectures,
used as surfactant templates, which result in 3D mesostruc- resulting in different mesophases toward enriched biomedical
tures with large pores (5–30  nm), for example, IBN-series.[14] applications. Further, the changes in the morphological attrib-
With respect to the concentration of surfactant, it plays a cru- utes, such as particle sizes and shapes, including Janus-type
cial role as the achievement of its CMC in the synthesis solu- architectures as well as deformable solids, are also discussed
tion appropriately guide the interactions between the silica (Figure 1).
species and subsequent cocondensation and growth of silica.
At the altered concentrations of surfactant, the synthesis may
lead to irreversible aggregation of silica, resulting in broad par- 3.1. Surface Engineering
ticle size distribution and irregular pores, which are not highly
expedient for biomedical applications owing to poor colloidal Indeed, the utility of MSNs is enormous in diverse fields
stability and suspendability, resulting in poor c­ irculation and owing to their advantageous hydrophilic surface containing
degradation. In some of the instances, the use of bile acids abundant hydroxyl groups as one of the predominant reasons,
as cosurfactants can tailor the physicochemical properties of which could be extensively tunable by the ease of introducing
MSNs, yielding diverse shapes, which could be well-suited the functional groups on both the exterior as well as inte-
for separation operations and morphology modulation of rior porous surfaces.[29–30] First, the surface coating of MSNs
MSNs.[23] However, change in the synthesis solution also play with supramolecular systems could offer the gate-keeping of
a crucial role, such as the utilization of sodium hydroxide and the guest molecules by ensuring their safety from premature
others. In this vein, triethanolamine is one of them providing release through controlling the opening or closing of the pore
the alkalescent environment, which results in ultrasmall, uni- entrances. In addition to therapeutic cargo safety for prema-
form-sized MSNs with exceptional colloidal stability (20  nm) ture release, they increase the physiological half-life of specific
by avoiding the particle aggregation and rapid hydrolysis. In biomolecules such as nucleic acids and enzymes.[31] Second,
addition, the use of various organosilanes for surface func- the biodegradability of the siliceous frameworks is merely pos-
tionalization could regulate the overall morphology of MSNs sible through coating stimuli-responsive components in the
and act as anchors for encapsulation of guests toward selective coated materials. Third, coating with several barriers, such
diverse applications.[24–25] as polymers with various surface functionalities, significantly
provides enough room for attaching targeting ligands that
enable the specific release of therapeutic cargo at the desired
3. Advanced Fabrication of MSNs site of action.[32] Finally, the altered surface chemistries over
nanocarriers facilitate the provision for overcoming specific
Considering the features of easy tailorable mesoporous frame- physiological barriers, such as macrophage uptake, in addi-
works, there has been significant interest in altering the overall tion to the augmentation of cellular internalization efficiency
morphology of MSNs to generate desirable properties of MSNs of the therapeutic cargo-carrying nanoparticles for safer
for their use in diverse applications.[26–27] Among various mor- biomedicine.[33]
phological attributes, particle diameter and modified shapes of
MSNs play crucial roles and significantly impact the behavior
of the delivery system, in addition to surface chemistry con- 3.1.1. Functionalization of Silicate Surfaces
cerning the extent of circulation in the blood and subsequent
immune responses as well as the delivery efficiency through Before the surface modification of the MSN surface, it is
stringent cellular uptake pathways.[28] These attributes sig- highly required to understand the versatility of the surface
nificantly influence the convenient delivery of guest mole- hydroxyl groups over the mesoporous frameworks, both
cules appropriately with augmented mass transport, which interior and exterior as well as necessity of functionalizing
is required for escaping the reticuloendothelial system (RES) the MSN surface as these have significantly highlighted the
uptake in the blood. These significant aspects of MSNs and potential of MSNs for utilizing them as selective adsorbents
their scope of advancements have enabled them to be one of as well as catalysts, biosensors, and other diverse biomedical
the predominant inorganic constructs as versatile delivery sys- devices. In addition, it gives us the explicit scope in tuning
tems and catalysis supports. the overall particle morphology of resultant organic–inorganic
In this section, we are focused on elaborating discussions hybrids. The available surface hydrophilic groups provide ease
based on the advancements in these mentioned three aspects. of immobilizing numerous organic functional groups over
First, we give an overview of modifying the MSN surface the mesoporous silica surface either by covalent conjugation
through surface engineering using various components such or by electrostatic interactions, which subsequently facili-
as polymers, liposomes, biomembranes, proteins, and metal tate the versatility and achieve control over the mechanized
shielding through direct immobilization or functionalization characteristics of these mesoporous constructs.[34] Covalent
of the mesostructured surfaces. Further, the alteration of sili- conjugations of functional moieties can be achieved either
ceous frameworks using various organic moieties (periodic by introducing the organosilanes during the condensation
mesoporous organosilicas, PMOs) as well as metal species, of the silica source, while fabrication of MSNs or by post-
i.e., metal-encapsulated MSNs (M-MSNs) leading to hetero- grafting approaches.[35] In both instances, the immobilized

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silanes leave the terminal functional groups available for sub- value of the surrounding environment, and molecules such
sequent cargo loading or polymer conjugation on the MSN as enzymes as well as glutathione (GSH), while the externally-
surface. In comparison, the postgrafting approach needs an applied stimuli comprise light, ultrasound, temperature, and
additional step for immobilizing functional saline, which magnetic field (Figure 3).[41–44] Polymers that respond to such
could be preferably undertaken before or after surfactant stimuli, either solely or in combination include chitosan,
template removal based on the scope for attachment of silane poly(2-(diethylamino)-ethyl methacrylate) (PDEAEMA), poly-
and requirements of conjugation.[36] Moreover, it is feasible to vinylferrocene (PVFc), poly(acrylic acid) (PAA), poly(N-iso-
immobilize functional moieties over the mesoporous surface propyl acrylamide) (PNIPAAm), poly(2-phenyl-1,3-dioxan-5-yl
through electrostatic interactions solely in the postgrafting methacrylate), and poly(allylamine hydrochloride) (PAH)/
approach due to extensively available surface silanol (SiO−) sodium polystyrene sulfonate cyclodextrin-based polypseudo-
groups. These silanol groups can expediently establish elec- rotaxanes, among others.[7] Employing external or internal
trostatic interactions with the cationic molecules, for example, stimuli, the release of guest molecules from the mesopores
poly(ethyleneimine) (PEI), for conveying the negatively charged can be well-achieved as they significantly impact the delivery
therapeutic cargo to enhance the cellular internalization pattern at the desired site by simultaneously reducing the
efficiency of MSNs.[37] adverse effects. However, the feasibility of these approaches
Despite their standout point of possessing the mentioned depends on the type of stimuli and the appropriate selection
abilities of encapsulating drug cargo and it’s protection from of the polymer, considering the degradation and compatibility
degradation enzymes, there is a necessity for functionalizing attributes.
the MSN surface as the naked MSNs could encapsulate the In this context, various strategies have been utilized to
therapeutic guest molecules through the physical adsorption as implement the coating procedure of these polymeric con-
well as weak electrostatic or hydrogen interactions, which sig- structs over the MSN surface by taking advantage of rich
nificantly decide the uptake efficiency based on the final active silanol surface chemistry. Although there exists a certain
surface area.[38] Moreover, these interactions lead to deprived degree of difficulty in directly modifying the hydroxyl groups,
loading efficiency as well as the uncontrolled release of thera- it is highly convenient to immobilize various other groups like
peutic cargo throughout the pathway, resulting in the poor bio- carboxyl or amine functional groups using various silane pre-
availability at the target site. Surface functionalization of MSNs cursors. In a case, the carboxyl group modified-MSNs offered
and subsequent immobilization of therapeutic cargo would not the covalent conjugation to a polymer for protecting the guest
only address these problems but also enable the release of ther- molecules until it was driven by a specific stimulus, which
apeutic cargo in a controlled manner at the targeted site, facili- was achieved through a physical or chemical modification
tating the decreased instances of unwanted adverse effects and (Figure  3A).[42–43] Notably, the possibility of drug leakage is
augmenting the overall therapeutic efficacy of guest molecules. high due to the mechanical aberrations during the processing
To this end, the approach of surface functionalization offers the involving multiple functionalization steps. An intriguing
versatility in the selective immobilization of appropriate func- series of attempts have been made to overcome the limita-
tional groups for conjugating the desired cargo, in which the tions of covalent linkage based polymeric coating approaches.
established interactions between the host as well as the guest In this framework, it is highly convenient to encapsulate
species through ligands facilitate the enhanced therapeutic negatively charged MSNs in the positively charged/cationic
efficiency.[39] polymers, such as PEI and PEI–cyclodextrin complex, among
others, which can enhance their interactions with the nega-
tively charged biological membranes through electrostatic
3.1.2. Polymer Coating interactions for various therapeutic cargo delivery such as
short-interfering ribose nucleic acid (siRNA) and enzymes.[31]
Regarding the drug delivery application, polymers are the most However, the major limitation with this approach is that there
preferred innovative materials as the tendency to improve the exists no cancer cell specificity during internalization, leading
fate and performance of any therapeutic molecule is high by to unwanted uptake by all the types of cells.[45] Although the
changing their delivery pattern in addition to offering struc- enhanced permeability and retention (EPR) and magic bullet
tural diversities and different functionalities.[40] Moreover, concepts work to a predominant extent in cancer therapy, it
these polymers act as controlled delivery vehicles for several may still lead to undesired accumulation of nanocontainers
guest molecules by prolonging the drug effect by maintaining in major organs of the body. In another attempt to address
the levels in the therapeutic window. Considering these sig- the capping of mesopores with polymeric surfaces, Palani-
nificant facts, enormous efforts have been put forward to fab- kumar et al. demonstrated a robust and facile one-pot syn-
ricating the versatile surfaces of MSNs by coating with several thetic approach for fabricating MSNs that end-capped with
polymers. Some of the examples include alginate, chitosan, a biocompatible self-crosslinkable random copolymer con-
polyethylene glycol (PEG), poly(2-(methacryloyloxy)ethyl fer- taining PDS and PEG as a targeted drug delivery platform
rocenecarboxylate) (PFcMA), Pluronic P123, pyridine disulfide (Figure  3B).[43] Further, a well-known Arg-Gly-Asp (RGD)
hydrochloride (PDS), PEI–PEG copolymer, and poly(2-vinyl ligand was immobilized for targeted drug delivery through
pyridine).[29] Moreover, some specific stimuli-responsive poly- receptor-mediated internalization. Similarly, various other
mers that are susceptible to different biological and external polymers such as PDEAEMA can be coated over MSNs toward
stimuli have also been utilized toward fabricating advanced fabricating a composite system that could respond to two or
delivery systems. Various biological stimuli include the pH more aforementioned stimuli (Figure 3C,D).[41,44]

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Figure 3.  Several examples showing the surface coating of MSNs with polymers that are responsive to various external and biological stimuli.
A) Schematic illustration of an acid cleavable linker involved mesoporous silica–polymer hybrid nanocontainer for controlled release of an anti-
cancer drug: synthesis of the particle, loading of the cargo, capping of the pore, and the delivery of anticancer drugs to the tumor. Reproduced
with permission.[42] Copyright 2014, Royal Society of Chemistry. B) Schematic representation of a one-pot synthetic procedure for polymer-gate-
keeper MSNs with the molecular-responsive polymer (PEG-PDS) and decorating the surface with a targeting ligand (cyclo(Arg-Gly-Asp-d-Phe-Cys),
cRGDfC). Reproduced with permission.[43] Copyright 2015, Wiley-VCH. C) Schematic representation for the structure of HMSNs-PDEAEMA and
different mechanisms of triggered drug release. Reproduced with permission.[44] Copyright 2015, American Chemical Society. D) Schematic illus-
tration of the behavior in an aqueous medium of the dual-responsive release system. Reproduced with permission.[41] Copyright 2015, American
Chemical Society.

In some instances, the delivery efficacy of MSNs has been irinotecan (CPT-11) from mesopores. Further, the experimental
improved by coating the hybrid layer systems with polymers as results in vivo in Balb/c nude mice have shown that the
one of its kind over their surface with another component.[39] CPT-11@PLS-MSNs revealed the most significant inhibitory
In this framework, liposomes have been predominantly uti- effect at the lower doses compared to free drugs and abridged
lized and generally accepted delivery systems for delivery var- the systemic toxicity accounting with CPT-11. Collectively, these
ious therapeutic cargo such as genes due to the resemblances results indicated that the stable composite layer-coated MSNs
with cell membrane in terms of both structure as well as com- could be used as a transmembrane delivery carrier toward effi-
position, capability in encapsulating a wide range of hydro- ciently conveying the therapeutic guests intracellularly.
philic and lipophilic drugs, targeting efficiency, and ease of sur- Despite their acceptability in utilization in vitro and few of
face PEGylation for evading macrophage uptake. Zhang et al. the models in vivo with specific characteristics, there is still a
developed an innovative hybrid system using a polymer–lipid long way to go for their use in human models as there are no
supported layer (PLS)-coated over MSNs for overcoming precise shreds of evidence and full understanding of the bio-
multidrug resistance (MDR) in cancer (Figure  4).[39] Plu- compatibility of MSNs in vast biological systems due to sophis-
ronic block copolymers in the layer acted as a drug efflux ticated attributes on the nanoscale range, such as effects of
pump inhibitor showing significant chemosensitization in particle size, shape, and surface chemistries, among others.
­
breast cancer resistance protein (BCRP)-assisted MDR tumors Apart from the compatibility of these silica constructs, the
along with the pH-sensitive liposomes for effective release of colloidal stability of MSNs also plays a crucial role in their

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through entanglement with natural biomembranes owing to

their similar composition. In this vein, this emerging biomi-
metic strategy of encapsulating various nanocontainers in the
extracted biomembranes offers enormous advantages such
as enrichment of drug delivery attributes along with compat-
ibility and degradability, improved long-term circulation by
reducing the macrophage attack, and delayed renal clear-
ance, among others. Toward establishing the biointerfacing
through direct replication, various membranes from dif-
ferent sources can be used for camouflaging of MSNs, such
as red blood cells (RBCs), macrophage, and cancer cells.[47–48]
Some of these membranes cloaked over nanoparticles can pro-
foundly exhibit various inherent capabilities of expressing some
proteins that can enable immune evasion and homologous
binding, similar to the source cells. In one case, Xuan et al.
fabricated magnetic MSNs (MMSNs) cloaked with cell mem-
branes for targeted cancer therapy toward achieving deprived
immune clearance and magnetic field-assisted accumulation
in tumors specifically. Ultrasonic bath-assisted deposition of
RBC membranes over the amine-modified MMSNs (≈80  nm)
resulted in the uniform reconstruction of RBC membranes
Figure 4.  Schematic illustration showing the cooperation between the
over the MSN surface (Figure  5A–G).[47] These biomembranes
responsive intracellular release of CPT-11 and the ability to overcome
drug resistance by blocking the efflux transporter. After the injection of not only facilitated the compatibility but also offered long-term
CPT-11@PLS-MSNs, the nanoparticles accumulated at the tumor site circulation for the enriched accumulation of nanocontainers
through the EPR effect in tumor blood vessels. The supported mem- at the target site. In another instance, Shao et al. fabricated
brane leads to ready depolymerization and triggered storm release of an the bioinspired diselenide-bridged MSNs based on cloaking
antitumor drug after internalization into tumor cells. P123-DOPE local- cancer cell membrane over them for dual responsive delivery
ized within the mitochondria and acted as a “door blocker” to deplete
(Figure 5H).[48] Despite the progress in evaluating their perfor-
adenosine triphosphate (ATP) and inhibit BCRP-mediated drug efflux.
Reproduced with permission.[39] Copyright 2014, Elsevier. mance both in vitro and in vivo, this area of research is still in
the infant stage, requiring further progress in terms of appro-
priate biointerfacing with the synthetic material and mecha-
applicability in biomedicine. Owing to their nature of composition nistic elucidations relevant to the interactions of the cloaked
and charged silica species, these MSNs are regarded as stable composites with the cells in vivo.
constructs in the physiological fluids.[45] Nevertheless, in some
instances, the stability of pristine MSNs is altered due to the
tiny particle size and surface. Similar to compatibility, the 3.1.4. Protein Coating
coating with polymers over the surface of MSNs can over-
come this critical issue. Moreover, these polymer coatings can In addition to various polymers, the coating of proteins is one
enhance the colloidal stability of MSNs by improving the repul- of the other exciting constituents that can be utilized for sur-
sive interactions with each other. However, it should be noted face engineering of MSNs toward the fabrication of innova-
that the optimal charge of the polymer plays a crucial role in tive nanocomposites. These appealing interfaces between the
establishing the electrostatic repulsions, leading to better ­biological molecules and synthetic inorganic materials serve as
­colloidal stability. an exciting platform for the manufacturing and development
of peculiar and interesting biomaterials for their extensive use
in diverse applications, such as drug screening, drug delivery,
3.1.3. Biomembrane Cloaking protein enrichment, and biosensing, among others.[49] This
happens to be conducive due to the stable siliceous frameworks
In addition to the bottom-up assembly of a liposome, a cell- that can able to safeguard the sensitive biomolecules from
membrane-mimic using various lipid-based components over denaturation and proteolytic hydrolysis. Over the past decade,
nanoparticles, the direct camouflaging of nanoconstructs numerous investigations have been reported on the delivery of
with the separated biological membranes has garnered enor- proteins and vaccines by enlarging pore sizes as well as their
mous interest in recent past toward biomedical applica- volume for conveniently enabling their encapsulation and
tions, with a focus on targeted tumor precision therapy.[46] delivery efficacy.[50–51]
Owing to their facile coating procedure and exhibition of Apart from their loading in the mesopores, the formation
multiple functionalities, these biomembranes are advanta- of a protein coat over the surface of the inorganic material
geous over the synthetic polymers as well as conventional through the contribution from the surface chemistries influ-
liposome coatings over nanoparticles. In addition, these encing the particle–cell interactions has been documented
membranes not only offer hemocompatibility attributes but so far.[52] More often, these conclusions have been well estab-
also facilitate augmented internalization of nanocontainers lished in the case of analyzing the fate and distribution of the

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advantageous with some of them in a way

similar to the coated polymers over the
mesoporous silica surface, including gate-
keeping for avoiding premature release
of the guest molecules as these biomac-
romolecule-gated systems are highly effi-
cient for practical applications relevant to
disease-related ailments. Moreover, stimuli-
responsive release involving glucose, pH-,
thermos-, and light-responsiveness have
been reported so far (Figure  6A,B).[36,53]
These stimuli-responsive proteins coated
over MSNs often favor the release of the
guest molecules, specifically through pro-
teolytic digestion and protein denaturation.
Several proteins have been used to coat
over the MSNs surface, such as hemoglobin
(Hb), albumin, biotin–avidin complex, Con-
canavalin A (Con A), streptavidin, and bioti-
nylated transferrin, among others.[36,53] The
selection of these biomacromolecules for
deposition over the negatively charged MSN
surface is predominantly based on the net
charge of the protein, which is evident that
the more net positive charge facilitates the
deposition of proteins over MSNs. However,
in some instances that based on applica-
tion, the surface engineering of MSNs with
protein differs by establishing the covalent
linkages over MSNs, and then subsequent
immobilization of protein may result in
stable corona throughout for biosensing
application. In addition, multiple synthesis
steps for surface functionalization are
required to fabricating an established for-
mulation of MSNs that surface engineered
with proteins covalently.
In contrast to polymers, it is feasible to
fabricate MSNs with a specific advantage of
autofluorescence property by coating them
with a specific protein corona over them.
In one case, Yang et al. fabricated glucose
oxidase (GOD) and the covalently linked
Hb as multilayers over MSNs through a
layer-by-layer approach for catalytic applica-
[54] These resultant com-
Figure 5.  Preparation and characterization of RBC@MMSNs. A) The preparation of RBC@ tions (Figure  6C).
MMSN and HB encapsulation. B) SEM/TEM image of MSNs. C) TEM image of MMSNs. posites with the controlled assembly of
D) CLSM image of RBC@MMSNs labeled by a cell membrane dye. Inset: TEM image of nega- protein layers could efficiently be internal-
tively stained RBC@MMSN. E) Diameter size and surface potential of RBC vesicle, MMSN, ized through the cell membrane, which was
RBC@MMSN. F) BCA assay kit for the measurement of RBC membrane-bound protein dis- evidenced by the autofluorescence efficacy
tributed on the surface of MSN, MMSN, and RBC@MMSN by using a UV spectrophotometer.
G) The protein payload yield of MMSN before and after RBC coating. A–G) Reproduced with
of the crosslinked proteins. Further, the
[47]
permission. Copyright 2018, Wiley-VCH. H) Schematic illustration of the synthesis proce- authors demonstrated the catalytic efficiency
dure of biodegradable diselenide-bridged MSNs and applications for dual-responsive, cancer- of these composites through enzymatic
cell-membrane-mimetic protein delivery. Reproduced with permission.[48] Copyright 2018, activity and glucose sensitivity through the
Wiley-VCH. generation of resorufin from the combined
reaction of Hb and GOD. These exceptional
material in the physiological fluids after administering in vivo. attributes made these biocompatible containers as a bio-
To this end, the surface engineering of MSNs with a protein marker as well as catalytic nanodevices in diverse biomedical
coat has garnered enormous interest due to their enormous applications.

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Figure 6.  Specific examples of protein-gated MSNs for diverse applications. A) Schematic showing the action mechanism of the light-responsive device
based on the Transferrin coated MSNs via biotin and streptavidin complex for photoresponsive release. Reproduced with permission.[36] Copyright
2015, Royal Society of Chemistry. B) Illustration of the controlled release of cargo from Con A-gated mannose-functionalized MSN nanocontainers
in response to changes in pH value and glucose concentration. Reproduced with permission.[53] Copyright 2013, Wiley-VCH. C) Schematic depicting
the immobilization of Hb and GOD on the surface of MSN with glutaraldehyde (GA) as a cross-linker for autofluorescence efficacy. Reproduced with
permission.[54] Copyright 2011, Royal Society of Chemistry.

3.1.5. Metal and Metal Oxide Shielding agents, via tethering molecular or supramolecular gating groups.
More often, the tethering of these supramolecular constructs
Metal and metal oxide nanoparticles (MNPs), either solid or in can be performed by immobilizing the acid-labile, molecular-
composite forms with various metals such as silica and others, responsive, light-sensitive linkers, which appropriately respond
have garnered considerable interest due to their exceptional opto- to a precise trigger and enables the release of loaded guest
electronic and physicochemical attributes, that are significantly molecules in the mesoporous nanocontainers toward diverse
different from their precursors or individual atoms or bulk mate- biomedical applications.[59–60] In this context, Liu et al. developed
rials. Moreover, these advantageous properties stringently depend pH-responsive nanogated valves based on Au-capped MSNs
on the size, shape, structure, and crystalline patterns of the con- through an acid-labile acetal linker (Figure  7A).[58] In another
struct.[55] In this context, these potential constructs offer enor- example from Zhu and co-workers, Au nanoparticles (AuNPs)
mous advantages, such as convenient fabrication of various sizes were gated over MSNs using the ATP aptamer, which could be
of MNPs using different transition metals (for example, gold (Au), selectively uncapped in the incidence of ATP molecules facilitating
iron (Fe), copper (Cu), silver (Ag), and cobalt (Co), among others) the governed controlled release of guest molecules by the target
with some of them exhibiting surface plasmonic absorption at a biomolecules at the desired site of action (Figure 7B).[61] Despite
size lower than 10  nm, which could be changed by altering the the several advantages of releasing guest molecules with the sup-
size, or aspect ratio resulting in nanorods. In addition, iron oxide- port of specific labile linkers and avoiding premature release
containing constructs are another classic example for improving and zero-ordered release, these gated systems still suffer from
the efficacy of existing therapeutic approaches, as their peculiar certain limitations, such as failure to establish the reversibility,
paramagnetic behavior allows them to be utilized for diverse bio- programmed operations in the aqueous environment, and
medical applications, notably, magnetic resonance imaging (MRI) appropriate exploration of the unique stimulus for drug release.
and magnetic field-assisted targeted drug delivery.[56] These thera- Further advancements have been made in developing the linkers
peutic strategies are highly recommended, and several advance- that could hold the MNPs and respond to one or more stimuli to
ments are underway due to their ability to overcome the problems release the guest molecules, for example, pH- and photo­induced
associated with the conventional therapeutic approach in terms of combinatorial release (Figure 7C).[62] However, the compatibility
the adverse effects and leaving the surrounding tissues safe. evaluation of these pore-blocking caps remained to be addressed
Considering these advantages of metal and metal oxide species as some of the MNPs are toxic and might generate severe adverse
in the forefront, several efforts have been put forward in the sur- effects and auxiliary inflammatory reactions when administered.
face coating of MSNs with such metal species as caps to predom-
inantly establish the zero-premature release property of guest
molecules (genes, biocides, drugs, proteins, and dyes, among 3.2. Framework Modification
others).[57–58] Along this line, different metal species such as cad-
mium sulfide (CdS), cerium oxide, iron oxide, and Au as well as The supramolecular arrangement of the condensed silica spe-
Ag-based nanoparticles, that have been engineered as capping cies has created enormous scope in preparing well-ordered,

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Figure 7.  Fabrication of metal-species-capped MSNs for diverse applications. A) Schematic illustration showing the pH-responsive nanogated ensemble
based on Au-capped mesoporous silica through acid-labile acetal linker. Reproduced with permission.[58] Copyright 2010, American Chemical Society.
B) Transmission electron microscopy (TEM) image of Au-capped mesoporous silica, and Au-capped mesoporous silica in the presence of ATP
(8 × 10−3 m). Reproduced with permission.[61] Copyright 2011, American Chemical Society. C) Schematic showing the encapsulation of guest molecules in
MCM-41 and subsequent gating of MNPs facilitating the pH and laser light-triggered release of the entrapped guest species (Safranine O). Reproduced
with permission.[62] Copyright 2009, American Chemical Society.

advanced mesoporous silica materials.[63] In addition to being during nanostructured synthesis, adsorption, chromatography,
compatible to a considerable extent, these stable siliceous enzyme immobilization, as well as protein separation and drug
ensembles with appropriate matrix have shifted the focus of the delivery, among others.[64–65] The PMO matrices are gener-
researchers toward modifying the highly stable siliceous frame- ally designed by hydrolysis and cocondensation reactions of
work by impregnating several substitutes, such as organic moi- organobridged silane, unlike traditional MSNs that utilizing
eties (PMOs) and metal species (M-MSNs), to achieve various the silica precursors (TEOS/tetramethoxysilane (TMOS)) alone
conducive attributes such as degradability in biological fluids via self-assembly-assisted sol–gel process. Since the inception
and enhancing the encapsulation efficiency of guest mole- of PMOs by Ozin, in the year 1999, several efforts have been
cules and creating new siliceous walls, such as caged porous made in fabricating PMOs with reduced sizes.[66] In the begin-
­architectures, among others. These modifications have opened ning, there has been a captivating interest in the generation
new opportunities for these promising materials in diverse of PMOs using limited groups, such as low molecular weight
applications such as biosensing, catalysis, microelectronics, organosilane precursors containing methane, ethane, ethylene,
and protein separation, in addition to drug delivery, bioim- and benzene bridging groups in the siliceous frameworks.[67]
aging, and other theranostic applications. Further, a variety of PMO frameworks with different shapes
(wormlike to spherical) at a vast size range of 20–500  nm
have been synthesized by varying the organosiloxane moiety,
3.2.1. Insertion of Organic Groups (PMOs) for example, ethylene, thiophene, biphenyl, divinylbenzene,
2,2′-bipyridine, and bis-imidazolium, among others.[38,64,68]
PMOs, an innovative class of mesoporous materials, can be The most predominant and fascinating structural attribute
fabricated with the hybridization of organic and inorganic of PMOs is the molecular rearrangement of their pore walls
components that are distributed homogeneously, forming during the condensation of organosilane, while conveniently
a covalently bonded mesoporous framework. These organic accommodating the organic bridge groups in the mesoporous
moieties substantially created an enormous impact on the frameworks. The arrangement of these groups facilitates the
mesoporous silica architectures in improving the function- tuning ability and augmentation of physicochemical attrib-
alities and morphological features of MSNs and offering new utes of the mesoporous frameworks. More often, the pore
burgeoning possibilities as well as exploring innovative appli- walls are assembled in a “crystal-like” lamellae ordering, in
cations. These are promising in catalysis, synthetic templates the case of benzene, as well as other hydrophobic-bridging

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Figure 8.  Schematic showing the mixed PMO-based MSNs. A) Design of mixed PMO nanoparticles, composed of the either bis(triethoxysilyl)ethylene
(E) or bis(triethoxysilyl)benzene (B), respectively. B) One-pot synthesis of AE or AB Au core–PMO shell nanoparticles, respectively composed of either
the E or the B moiety. C) One-pot synthesis of AE2 or AB2 Au core mixed PMO shell nanoparticles, Composed of either 2PS and E (AE2), or 2PS and
B (AB2 nanoparticles). A–C) Reproduced with permission.[70] Copyright 2014, American Chemical Society.

groups through hydrophobic and hydrophilic interactions in several attempts have been put forward in the development
the aqueous environment.[69] of biodegradable PMO frameworks based on precursors with
Furthermore, the arrangement of pore walls as regularly stimuli-responsive linkers. In one case, Croissant et al. fab-
packed columnar assemblies in PMOs was confirmed by the ricated ethylene-bis(propyl)disulfide-based PMOs with dif-
Inagaki group, stating that the presence of hydrogen bonds ferent shapes, i.e., nanorods in size range of 130–450  nm
in the organosilane precursor would facilitate a new kind of and uniform-sized nanospheres of 200 nm in size for efficient
molecular-scale ordering of pore walls in PMOs.[69] These drug delivery.[65] Interestingly, the utilization of specific
consequences enable the PMOs with the hydrogen-bonded organosilane precursor has guided the overall morphology
organosilica in their frameworks that can facilitate the accom- of the PMOs, where nanorods were obtained with ethylene
modation of guest molecules with hydrogen bonding. In and spherical nonporous particles with bis(propyl)disulfide
addition, the variation in the bridging moiety has facilitated bridging groups. Further, the mixture of these silanes in a ratio
­enormous hope in the utility of PMOs toward the biomedical of 1:1 has shown an exceptional biodegradability in physiolog-
applications in terms of improving the compatibility, degrada- ical fluids (Figure  9).[65] Besides the biodegradability of these
bility, and reduced sizes for efficient delivery applications. In nanoconstructs, the payload of guest molecules was enhanced
some instances, it has been reported that incorporating mixed by altering the organosilane moiety in the mesoporous frame-
organosilane precursors while fabricating PMOs would facili- works. Although the payload is comparatively higher in the
tate the remarkably high specific surface areas with enhanced acidic conditions, strict ­optimization of encapsulation param-
drug transportation ability and synergistic biomedical applica- eters and mechanisms lying behind the loading efficiency
tions (Figure 8).[70] and favorable release specifically in the acidic environment
Although PMOs were first synthesized more than a decade for cancer therapeutics or targeted delivery specifically in the
ago, significant attention toward the biomedical field has been desired site of action remained to be explored.
drawn very recently. Among the next challenges in the utility
of MSNs in this field, the fabrication of biodegradable siliceous
frameworks based on PMOs by incorporating the larger func- 3.2.2. Impregnation of Metals
tional organic groups in the siliceous frameworks seems to
be more promising in the fabrication of such hybrid systems, Despite the thermal as well as mechanical stabilities, the neu-
specifically for biomedical applications.[65] In this framework, tral, as well as the amorphous character of pure silica, limit the

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Figure 9.  Biodegradability of PMO-based MSNs. A–F) TEM images showing PMO nanospheres with mixed silanes in 50/50 before (A) and after
(B–F) 48 h of degradability in physiological conditions. A–F) Reproduced with permission.[65] Copyright 2014, Wiley-VCH.

applicability of MSNs in some versatile fields such as molecular Concerning the beneficial properties and peculiar phys-
adsorption and catalysis. In recent times, enormous efforts have icochemical attributes, MSNs still face a major limitation of
been put forward in altering MSN frameworks by impregnating deprived encapsulation efficacy as they involve weak host–
the metal species in their siliceous pool, owing to their addi- guest interactions resulting in the physical adsorption, which
tional properties, which provide enormous potential in diverse may lead to a subsequent exchange of encapsulated guest
applications.[71] For the first time, aluminum was incorporated species with the surrounding ions during loading. To address
in the siliceous frameworks through a simple cocondensa- this limitation, multiple studies from our group have reported
tion method, which has added enormous advantages, such as the modification of mesoporous frameworks by various diva-
augmenting the surface acidity, and chemical functionality of lent and trivalent metal species, notably, Cu(II) and Fe(III) to
alumina to MSNs, resulting in the enhanced performance in establish the coordination interactions with the guest species.
catalysis.[72] Along this line, numerous other metal species have To this end, these stable interactions offer numerous advan-
been impregnated in the mesoporous frameworks such as Co, tages of enhancing their loading efficiency in the mesoporous
Fe, Cu, and Ni for diverse applications.[73] Initial consideration frameworks and facilitate their discharge, specifically in the
of metal incorporation lies in the fact of the critical optimization acidic microenvironment, by shedding the pH-responsive coor-
of metal concentration to that of silica. Incorporation of metals dination interactions through selective protonation of the guest
in the siliceous frameworks often leads to the reduced concen- molecules in tumor ailments and certain infection sites.[74]
tration of the silanol groups, which may result in the deprived Moreover, the cellular internalization of these composites can
loading of the guest molecules to be adsorbed in the mesopores. be enhanced through augmenting the molecular interactions
However, it should be noted that critical care is mandatory while with the negatively charged cell surfaces during the delivery of
optimizing the synthesis conditions in terms of reactant concen- guest molecules. However, the establishment of coordination
trations, particularly, the ratio of the concentration of metal to linkages with the guest moieties is favored for only the guest
silica. At the greater quantities, it may result in the distortion of molecules with nitrogen atoms, which could able to establish
the mesoporous frameworks ensuing in the disordered siliceous such interactions and protonation efficiency (Figure 10).[75]
frameworks in irregular shapes and separation of metals in In addition, the function of metal species as nanomachinery
the form of corresponding metal oxides. Further consideration elements can be able to transform the naturally available
includes the arrangement of pores while rearranging the metal molecules at the diseased site to deadly cytotoxic molecules for
species in the siliceous frameworks. However, it should possess exhibiting therapeutic function. Such a typical catalytic func-
deep pores with large volume, to substantially overcome the tion could be exhibited by some of the transition metals, for
narrowing of pores while accommodating the guest molecules, example, Cu and Fe, which have a catalytic ability to produce
which may influence its loading efficiency. active free radicals intracellularly, i.e., reactive oxygen species

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sizes).[6] Typically, the ability to tune the mesopores could be

achieved well by using the nonionic surfactants over the ionic
surfactants. For example, the use of numerous block polymers
such as diblock polystyrene–poly(ethylene oxide), as well as
PEO–PPO–PEO, and triblock polystyrene–polybutadiene–poly-
styrene, copolymers resulted in the pore size of 5–30 nm.[76–77]
Other approaches based on the usage of lyotropic surfactants
such as cetylpyridinium chloride as a template, which could
result in enhanced and adjustable mesopore sizes in the range
of about 6–35 nm range. Although there is a promising poten-
tial in producing various silica monoliths for many mesoscopic
applications and achieving effective control over their size and
shape using these Brij series (Brij 76 and 56) of surfactants, the
mesopores sizes are stringently dependent on the type of com-
position of the surfactant.
Even then, the research on enhancing the pore size of
MSNs has been continued for encapsulating the large-sized
molecules. In this context, several swelling agents such as
Figure 10.  Metal-doped mesoporous siliceous frameworks for stimuli- long-chain alkanes, for example, n-octane or decane, and long-
responsive drug delivery. Schematic representation illustrating the Cu chain trialkylamines or N,N′-dimethylalkylamines have been
metal-doped MSNs the mechanistic illustration of pH-responsive delivery used to expand the pore size to about 8–11 nm. Incorporation
in the tumor microenvironment. Reproduced with permission.[75] Copy-
right 2015, Royal Society of Chemistry.
of these pore expanders into the template assembly signifi-
cantly augment the overall volume of the assembled surfactant
micelle through their solubilization in the hydrophobic cores
(ROS) from available hydrogen peroxide, whose levels are of the surfactant aggregates. Another classic example of such
comparatively higher to that of normal cells, leading to lethal pore expanders is the trimethylbenzene, which could enlarge
damage of tumor cells at the cost of their exhausted antioxidant the size of the mesopores to ≈10–42 nm. Despite the enhance-
defenses. Motivated by this fact, multiple metal species (Cu and ment of the sizes of mesopores to a considerable extent for
Fe) were impregnated mesoporous siliceous frameworks for encapsulating the bulk molecules, the major limitation of
chemodynamic therapy, in which the doped metal species sig- these mesopores is that they failed to maintain the long-range
nificantly altered the shape of MSNs due to the repulsions of ordered mesostructured architectures. In this vein, the genera-
positively charged species.[73] Moreover, these metals enhanced tion of enlarged mesopores sizes either by using the enhanced
the loading efficiency of the drug and facilitated its release concentrations of auxiliary expanders like hydrocarbon alkanes
through pH-responsive metal–ligand interactions. Although or by phase transitions through altering the pH conditions
the investigations relevant to some of the transitional metals can be achieved. However, the geometrical phase changes
evidenced the above discussed beneficial attributes, much could not control the significant challenge of the collapse of
research in such areas by encapsulating multiple metal species crystalline mesostructures.[78] To address this limitation, in a
in the single nanocontainers and studies on different metals case, Niu and co-workers successfully fabricated uniformly
species other than Cu and Fe, yet to be performed. The inves- dispersed large-pore MSNs by the facile self-assembly/solvo-
tigations in this vein would open a promising potential in the thermal strategy using diblock copolymer PS-b-PAA as a tem-
applicability of M-MSNs. plate, where the MSNs distributed with ordered and intercon-
nected mesochannels (>12  nm) in the structure were altered
by changing the concentration of structure-directing agent
3.3. Tuning the Mesopores (CTAB). Notably, the altered concentration of CTAB resulted
in the cubic, hexagonal, and lamellar porous architectures
According to the International Union of Pure and Applied (Figure 11A,B).[79] In another case, they fabricated the biocom-
Chemistry (IUPAC) nomenclature, the name MSNs, a family patible hollow MSNs (HMSNs) with diverse controllable pore
of highly porous materials, was coined based on the great sizes in the range of 3.2–12.6 nm using C18 TMS for efficient
porosity with an average size in the range of 2–50  nm, which and controllable loading of guest molecules enabling their dif-
allows this inorganic silica-based platform to harbor substan- fusion and control the drug release rate (Figure  11C).[80] The
tial amounts of cargo for delivery without destabilization of the formation of different pore sizes in the silica shell is due to
inert siliceous frameworks. Several advancements in tuning the difference in the etching time of core silica, resulting
the size of mesopore have recently been evidenced by using in the hollow nanostructures. However, the clear evidence
the conventional synthetic routes relying on various modifica- that drawing the conclusion of different pore sizes in the
tions involving the innovative chemistries for the generation outer silica shells due to different etching time remains to
of sophisticated mesoporous architectures. Multiple studies be explored. In addition, efforts on increasing the overall
have been performed on the fabrication of materials with dif- volume of the pores have also been made by regulating other
ferent mesoporous characteristics (i.e., unimodal or bimodal experimental conditions like increased temperature, external
porosity, ordered or disordered porous networks, and pore treatment with N,N′-dimethyldecylamine.

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Figure 11.  Tunable mesoporosity for advanced drug delivery. A) Schematic illustration of the formation mechanism of ordered large-pore silica nano-
spheres (LPSNs) with tunable pore structure: a) lamellar, b) hexagonal, and c) cubic. Step A: the increasing concentration of CTAB induces the mor-
phological transformation of the silicate/PS-b-PAA micelle aggregates. Step B: the packing together or aggregating assembly in an ordered fashion
to form the long period stacking structures with lamellar, hexagonal, and cubic. B) TEM images and corresponding Fourier diffractograms (insets) of
LPSN-C300 along the [110] (a), [311] (b), and [111] (c) directions. A,B). Reproduced with permission.[79] Copyright 2014, Wiley-VCH. C) Representative
schematic illustration of controlling doxorubicin (Dox) release rate by tuning the pore sizes of HMSNs to 3.2 nm (HMSNs1), 6.4 nm (HMSNs2), and
12.6 nm (HMSNs3). It was anticipated that the small pores provided limited room for the diffusion of Dox, while large ones could provide enough
room for the fast diffusion of drug molecules, which would lead to the higher release rate of drug molecules. Reproduced with permission.[80] Copyright
2011, American Chemical Society.

3.3.1. HMSNs ultimate sizes of HMSNs can be augmented by the packing

of micelles as vesicular structures at a high packing parameter
Silica nanoparticles with a hollow interior and mesoporous value, which apparently leads to the generation of large-sized
shell (namely, hollow MSNs or HMSNs) are another class of hollow spheres (>100  nm). These vesicle templates could
innovative mesoporous silica materials predominantly devel- accommodate supramolecular nanoarchitectures due to their
oped to overcome the limitations of traditional MSNs in the high flexibility in housing them, eventually resulting in the
conveyance of bulk drugs like proteins and others by exhib- formation of globular hollow architectures or core–shell com-
iting the mass diffusion property with advanced storage ability posites. In addition to the simple soft templating approaches
as well as the conveyance of the bulk guest molecules. These based on micelle and vesicles, a microemulsion system using
hollow nanocontainers are generally prepared by various stable hybrid phases (oil-in-water, O/W) along with surfactants,
methods based on soft-/hard-templating strategies to con- as well as a slight amount of alkaline solution, is used to
trol the inner core that guide the generation of hollow archi- fabricate HMSNs. Further, several advancements in the aug-
tectures upon removal of the templates. One of them is the mentation of mesopore sizes have been made using the expan-
soft-templating method, in which micelles, vesicles, and micro- sion agents and triblock copolymers, such as kippah-shaped
emulsion droplets are used as templates. This approach is HMSNs.[83]
often based on the utilization of a wide variety of amphiphilic On the other hand, the hard-templating method is the
surfactants, which could be well explored in making the tiny most-effective approach, which can be used in assisting the
hollow nanocontainers.[81] More often, the mesopore size and generation of monodispersed HMSNs. This practical strategy
shape of eventual MSNs depend on the packing of the micelle; includes the use of dissolvable or combustible interiors, such as
however, concerning HMSNs, the arrangement of single polymer beads (poly(methyl methacrylate) (PMMA); PS; PNI-
micelle packing as spherical micelles results in the hollow and PAAm; and polyvinylpyrrolidone (PVP)), metal/metal oxides/
small globular nanoarchitectures in size range of ≈20 nm. Nev- semiconductor or calcium phosphate nanoparticles, such as
ertheless, it should be noted that the delivery of drugs is highly Au, Ag, CdS, ZnS, hydroxyapatite, and silica spheres, among
challenging using these tiny architectures due to the limited others, as the hard templates.[6] Among them, the polymer
size of the micelles. To solve this issue, HMSNs were fabri- beads as hard templates ranging from several tens of nanom-
cated by incorporating several hydrophobic expansion agents eters to greater than a micrometer are often preferred as they
or micelles based on long-chain asymmetric block copolymers, are inexpensive and can be most appropriate for the fabrication
for example, core–shell–corona micelles based on polystyrene of discrete, uniform, and monodispersed particles. Indeed, they
homopolymer (homo-PS) as a core with poly(styrene-b-2-vi- can be conveniently removed through simple extraction pro-
nylpyridine-b-ethylene oxide) (PS–PVP–PEO).[82] In this case, it cedures like acid-­dissolution, calcination (around 400  °C), and
is expedient to control the overall inner hollow void space by solvent extraction under mild conditions without disturbing the
altering the micelle core in the nanosize range. Further, the inorganic silica cast.[84] Contrarily, the utilization of expensive

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inorganic solids as the templates require a corrosive solution requirement of additional organic anchors referred to as core–
to get them off from the core. Moreover, it should be noted shell or yolk–shell architectures, which are of specific interest
that the removal procedure is highly hazardous, and special in diversified fields of medicine and catalysis.[86] Further, the
­precautions are required to be followed. However, in addition synthesis can be progressed by using a generally applicable
to the removal procedures, there are some other specific cri- approach, i.e., the modified Stöber process, mediated by qua-
teria to be considered while fabricating HMSNs based on the ternary ammonium surfactants using a single-step procedure
hard-templating approaches. One of the critical aspects is the (Figure  12). These surfactants coated initially over the metal
silicification over the surface of a hard template, which should core, not only act as pore-directing surfactant templates but also
be faster over the self-condensation rate of silica. On the other facilitate the capping of many nanoparticles in overcoming the
hand, the surfactant template deposition for surface mesopores instability as well as compatibility issues, in a case with core
generation should be appropriately distributed and stable and shell possessing similar charges. In addition to this struc-
throughout the condensation and silica casting process. Con- ture-directing agent, several shielding agents, such as polymers
versely, the unstable organic template deposition would result like PVP, have been used to preserve the stability and safe-
in the futile molding of silica. This method can be utilized guard the unique characteristic features of MNPs. For example,
in accommodating stable MNPs in the core of hollow spaces Lin and co-workers fabricated core–shell nanocomposites based
resulting in the fabrication of core–shell nanoconstructs for on platinum (Pt) nanoparticles, PVP, and MCM-41 using a
catalytic or advanced biomedical applications with augmented liquid-phase self-assembly approach to augment the reusability
synergistic theragnosis. as well as the lifetime of the core Pt nanoparticles (Figure 12A).[87]
In addition, there has been increasing interest in the uti- However, strict optimization of reaction conditions could
lization of hard inorganic nanoparticles, such as semicon- result in MSN-based core–shell nanohybrids.[88–89] Similarly,
ductor nanoparticles or metal/metal oxides for the surface several studies have been reported in exploring the advanced
activation on hard templates.[85] Upon surface activation, applications of core–shell nanoparticles using iron oxide, zinc
the composite of MSNs with the inorganic template would oxide, Au, Pt, and Ag-based NPs in size range of 20–50  nm
result in the fabrication of customized hybrid particles in the in the optimal reaction conditions with the contribution
optimal reaction conditions, which could synergistically aug- of individual components (Figure 12B,C).[87,90] In this vein, sev-
ment the functionalities with distinct advantages offered by eral attempts in adjusting the thickness of the silica shell have
the individual components. The thermally stable mesoporous been made by optimizing the amounts of the nanoparticle to
silica coating over the nanoparticles could also result in the surfactant and silica source ratios.[89,91] Despite the significant
reduction of undesired aggregation and enhance their perfor- progress in the fabrication of metal-encapsulated HMSNs as
mance, dispersity, and stability as well as robust protection core–shell nanoconstructs, there is a significant limitation in
against the sintering of nanoparticles. Subsequent removal of the controlled synthesis of small-sized HMSNs with MNPs in
the core nanoparticles by etching approach using acids can their cavity. In addition to various approaches available for the
eventually generate HMSNs with large interiors. However, generation of HMSNs, numerous other strategies have been
the removal of hard templates is sometimes time-consuming developed for the generation of the yolk–shell MSNs, a sister
and uneconomic. class of HMSNs, including bottom-up, ship-in-bottle, selective
More often, these inorganic metal lattices in the core that etching, template-free, Ostwald ripening, and Kirkendall effect-
are conveniently coated with a stable mesoporous silica shell based approaches.[6] However, the convenient generation of
by directly depositing over the metal templates without the these architectures happens to be favorable by the utilization

Figure 12.  Core–shell architectures of metals/metal oxide-encapsulated MSNs. A) Schematic representation illustrating the preparation of
Pt@mSiO2 and B) their respective TEM images: a) Pt nanoparticles and b) core–shell nanospheres. A,B) Reproduced with permission.[87] Copyright 2004,
Wiley-VCH. C) TEM images of gold nanorods (AuNRs)@mSiO2. Reproduced with permission.[90] Copyright 2008, American Chemical Society.

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of a binary surfactant mixture of zwitterionic and anionic sur- as they result in rapid mass transport of the guest molecules
factants, which result in a vesicle-like structure to encapsulate providing long-term circulation in the blood, in addition to
stable metal nanoconstructs. excellent suspendability and adequate adhesion to the biolog-
ical membranes. Moreover, it is increasingly recognized that
the particles at this size range could combat the RES uptake
3.4. Nanoarchitecting Morphology efficiently.
Although the appropriate size for the efficient delivery of
3.4.1. Size-Designed Particles drugs remained to be recognized as the submicrometer in size
at around 100 nm, the synthesis of MSNs within the specified
Despite the success in delivery efficiency through encapsulating size range is highly challenging as it often results in the disor-
various hydrophobic and charged guest molecules, the critical dered mesostructures. Further advancements have been pro-
challenge resides in critically optimizing the design features, gressed in the fabrication of MSNs lesser than 100 nm. How-
specifically, the eventual size for the efficient and safe delivery ever, the well-ordered mesostructures failed to achieve excel-
of encapsulated molecules. In the case of biomedical applica- lent polydispersity leading to severe irreversible aggregation,
tions of MSNs where they precisely deliver anticancer drugs which made them inappropriate for biomedical applications.
with varied charges into the tumor tissues, augmented EPR These issues remained as synthetically challenging in the
effect (large fenestrations with insufficient lymphatic drainage designing of MSNs with appropriate sizes that could be well-
leading to high retention efficacy), and subsequent uptake of suited for biomedical applications. To overcome such prob-
cells play crucial roles as the particle size significantly impacts lems, Lu et al. demonstrated the synthesis of monodisperse
the efficiency, and pathway, as well as rate of uptake into the MSNs and their uptake efficiency concerning the particle
cells. While considering the safe delivery of guest species from size (30–280  nm), which were tightly controlled concerning
mesoporous frameworks, several aspects that promise safe and the charge instantaneously (Figure  13A).[26] The particle sizes
effective delivery should be predominantly considered, such were critically reduced by following the modified Stöber pro-
as RES uptake, as well as enhanced cellular internalization of cess at the low surfactant concentration and altered pH values
the targeted tissue.[92] In this framework, it is required to focus of the reaction medium. It was suggested that the particles
considerably on the localization and stable residence of nano- with a diameter around 50  nm were the most suitable candi-
particles at the targeted site, besides sustained delivery and bio- dates, but further cell responses concerning the size remained
compatibility issues. It should be noted that the smaller-sized unclear. Similarly, in another case, the hemolytic activity of
particles achieve better extravasation of the tumor environment. MSNs on RBCs concerning different sizes by altering the syn-
Due to their small sizes, such composites conveniently return thesis mixture of TEOS and ammonium hydroxide was dem-
to the physiological circulation, resulting in the low retention onstrated (Figure  13B).[28] Herein, the integrated mesoporous
efficacy. However, other morphological attributes, as well as structure at smaller sizes has shown higher toxicity, however,
surface properties, would aid in influencing the delivery pattern lesser than those of its nonporous counterparts. Further, the
of drugs through the EPR effect. ameliorating effects have also been suggested, such as surface
In the beginning, there has been a slight focus on the modifications with polymers (PEG and its copolymers like
effect of particle size on their behavior toward the applica- PEI-PEG) for addressing the opsonization as well as stability
bility of MSNs. However, no precise mechanism involved in attributes and concomitantly the passive delivery of small-
these effects has been explored. Moreover, the shreds of evi- sized nanoparticles in the tumor microenvironment effec-
dence have been correlated to the specific theoretical models tively.[96] However, it was suggested that these were the short
based on the established interactions with the surface recep- term solutions for their safe utilization in biomedical applica-
tors or membrane elasticity associated with the internaliza- tions. Moreover, multiple synthetic steps would lead to a loss
tion pheno­ mena. Considering these facts, several groups of mesoporous integrity due to mechanical abrasion during
have increasingly recognized that the particles, even MSNs surface modifications.
at large sizes, could agglomerate in the biological media.
Thus, these consequences insisted the researchers in dem-
onstrating the size effects of MSNs that could efficiently 3.4.2. Modified Shapes
helpful in determining precise therapeutic effects through
passive targeting.[93] Most of the instances, the MSNs with Despite their stable and rigid siliceous mesoporous frame-
altered diameters are generated by varying the base catalyst, works, there is enormous scope in altering the shapes and well-
the pH value of the reaction medium and the structure- ordered regular geometry of MSNs due to the tunable overall
directing template, as well as its concentration, required for morphological attributes. Such modifications can lead to the
silica condensation. In this framework, Vallhov et al. demon- development of advanced bio-/nature-inspired nanoarchitec-
strated, for the first time, the effects of altered particle diame­ tures such as flower-shaped structures and deformable solids,
ters (270–2500  nm) on the immune responses of dendritic among others, with application requirements as paramount
cells.[94] In another case, Hudson et al. explored the biocom- concerns.
patibility attribute of MSNs with different particle diameters Janus Nanoarchitectures: Janus-type hybrid composites based
(150–4000  nm).[95] Collectively, these reports indicated that on MSNs are one such anisotropic nanoarchitectures with irreg-
the particles with an optimum size in the nanoscale range are ular shapes, which have garnered enormous interest in various
convenient for internalization over micrometer-sized particles fields of research to augment the intrinsic functionalities,

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Figure 13.  Effect of particle size of MSNs on biomedical applications. A) Confocal laser scanning microscopy (CLSM) images of HeLa cells after incu-
bation for 5 h at 37 °C with fluorescein isothiocyanate (FITC)-MSNs (100 µg mL−1, green) of size 170 nm (a), 110 nm (b), 50 nm (c), and 30 nm (d).
The cell skeleton was stained with rhodamine-phalloidin (red), and the cell nucleus with 4′,6-diamidino-2-phenylindole (DAPI; blue). Reproduced with
permission.[26] Copyright 2009, Wiley-VCH. B) TEM images of MSNs with varied diameters: a) 24 nm, b) 37 nm, c) 142 nm, and d) 263 nm, impacting
hemolytic activity. Reproduced with permission.[28] Copyright 2010, American Chemical Society.

physicochemical characteristics, and stability attributes, leading evaporation and vacuum sputtering.[18,99] These approaches
to enhanced performances of the overall construct over con- could generate the architectures by depositing metal spe-
ventional MSNs.[97] In this framework, these asymmetric cies on the surface of MSNs either as irregularly deposited
mesoporous-silica-based nanoarchitectures could offer distin- islands (Figure  14B) or in a hemispherical cap-like structure
guished surface properties exhibited by different compositions (Figure 14C,D), which are in contrast to the asymmetric multi-
along with different electrical, optical, and magnetic proper- compartment species mentioned above.[18,99] The uneven dep-
ties, compared to conventional MSNs.[98] In addition, these osition of metal islets on the surface of MSNs would power
constructs overcome the undesired aggregation of MSNs due these constructs as nanocatalysts and therapeutic cargo vehi-
to the altered charge densities by incorporating multiple spe- cles.[102,103] Despite the efficiency of self-thermophoresis for
cies, including MNPs, on the surface or within the mesoporous potential cargo delivery, it still suffers from certain shortcom-
frameworks.[99] In general, these sophisticated asymmetric ings, such as limited to loading specific small molecules and
constructs have been first prepared to combat the usage of
­ the possibility of damaging the loaded sensitive molecules
conventional Janus units that are based on silica and other while coating or depositing metal shields. In addition, the
dense polymers toward addressing a significant limitation of safe transportation of drug cargo is highly challenging as the
poor loading efficiency of guest molecules.[100] Similarly, con- powered motors rotate at high speed in the biological environ-
ventional MSNs also suffer from the lack of enough space for ment. However, it could be possible to combat these issues by
encapsulating multiple guest molecules for controlled release integrating certain molecular gatekeepers on the mesopores.
in their respective desired sites.[101] Moreover, installing asymmetric capping based on organic
Thus, in demand of addressing the above-discussed issues, moieties through well-defined functionalization chemistries
several advancements have been made to fabricate versatile could circumvent the issues associated with fabricating asym-
designs based on mesoporous-silica-assisted Janus nano- metric structures based on inorganic nanocomposites. In
architectures for the encapsulation of multiple agents with comparison, their particle sizes being lesser than 100  nm.[104]
independent storage. However, it should be noted that the Together, these highly dispersible asymmetric nanoarchitec-
chemical composition, as well as the crystal structures of the tures were beneficial for phase-selective catalysis and drug
individually employed components, play significant roles in delivery applications.
the fabrication of Janus-type assemblies. In one case, Li et al. Although there have been significant signs of progress
fabricated complex Janus-type architectures based on the upcon- in the advancement of the Janus architectures, these archi-
version nanoparticles (UCNPs) (NaGd-F4:Yb,Tm@NaGdF4). tectures suffer from several shortcomings, such as multi-
Further, anisotropic growth of silica over the surface of the step fabrication resulting in fragile MSNs, and utilization
UCNPs through heterogeneous nucleation resulted in the of multiple inorganic metal species leading to biocompat-
dual-independent mesophases for loading the two different ibility issues regarding biomedical applications. To overcome
guests in them, facilitating the codelivery of multiple drugs these issues, we recently fabricated MSNs-based Janus-type
with different physicochemical attributes to the desired target nanoarchitectures through a facile, one-step based on the
sites (Figure 14A).[100] Apart from the chemically powered syn- modified Stöber process by incorporating the first-row tran-
thesis, it is feasible to fabricate such innovative Janus-type sition metals, Cu and Fe, in the mesoporous frameworks
architectures using various other approaches of electron beam (Figure  14E).[73] While fabrication, these transition metals

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Figure 14.  Fabrication of Janus nanoconstructs for advanced applications. A) Synthetic procedure for the dual-compartment Janus MSNs, UCNP@
SiO2@mSiO2&PMO by the anisotropic island nucleation and growth method (UCNP = NaGdF4:Yb,Tm@NaGdF4, mSiO2 = mesoporous silica shell).
Reproduced with permission.[100] Copyright 2014, American Chemical Society. B) Characterization of Janus MSNs with different sizes coated with Pt
(2 nm) installed by electron beam deposition. C) STEM-HAADF image and element mapping of Janus MSNs. Reproduced with permission.[18] Copy-
right 2015, American Chemical Society. D) Schematic illustration of AuNP-coated Janus MSNs by vacuum sputtering. Reproduced with permission.[99]
Copyright 2016, American Chemical Society. E) Schematic illustration showing the fabrication of various metal-doped MSNs via a simple route, along
with the optical images showing the color change and TEM images revealing the morphology of different surfactant-extracted Cu–Fe MSNs. Elemental
mapping based on TEM presenting the arrangement of varied chemical species along with the incorporation of metals in the Janus-type mesoporous
frameworks. Reproduced with permission.[73] Copyright 2019, Elsevier.

are conveniently arranged on the pre-MSN core, ensuing structures through multipodal colloidal clusters of silica with
in the Janus (sphero-ellipsoid) nanocontainers due to the augmented electrical, physicochemical, and optical proper-
repulsive forces among the transition metals. In addition ties toward diverse applicability. One of the classic examples
to a­ugmented drug loading efficiency through establishing of such multipodal silica architectures from Suteewong and
coordination interactions, these metal species arranged co-workers was the fabrication of 2D hexagonal silica pods on
in the silica pool considerably enriched the generation of the silica cores with cubic porosity using epitaxial growth.[105]
Fenton-like ­reaction-assisted free radical species, specifically Further, these advancements were foreseen with enhanced
in the cancer cells rather than healthy cells. ­characteristics using PMOs by Croissant et al.[97] In this context,
Multipodal and Deformable Shapes: Similar to other inorganic the hybrid, crystal-like PMO-based multipodal architectures
materials like quantum dots and lanthanide materials, MSNs were fabricated using one-pot, a two-step approach, in which
have also been fabricated with high morphologically complex the ethylene-bridged pods were successfully condensed over

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the benzene-bridged PMO core (Figure  15A).[97] Moreover, the Apart from the morphological attributes, most importantly,
authors further demonstrated that it was convenient for selec- deformable solids with elastic properties showing reversible
tive absorption of drugs in the core as well as the pods, which arrangement have attracted enormous attention in the bio-
could render multiple drug delivery at the desired sites, similar logical applications as they could show promising potential in
to asymmetric Janus architectures. In another attempt from Xu paving the interactions with the biological membranes as well
and co-workers, the core-cone structured MSNs were fabricated as subsequent internalization over the stiff MSN solids. In
by supramolecular packing of silica lamellae over a spherical addition to interactions with biomembranes, these could play
pre-MSN core in a chlorobenzene–water system resulting in a crucial role in the long term circulation as well as bioavaila-
the flower-shaped MSNs for protein delivery (Figure  15B).[106] bility in tumors. However, it should be noted that these innova-
Interestingly, these large-pore-sized MSNs with enormous pore tive constructs could not be compared with the soft materials,
volume could conveniently encapsulate high molecular weight such as polymeric constructs and liposomes, as the following
proteins at a high encapsulation efficiency for their intracellular constructs lack the mesostructured characteristics and stable
delivery. Although the fabrication of MSNs resulted in morpho- frameworks.
logical and structural complexity, the arranged surface cores Despite the intrinsic rigid chemical bonds in the siliceous
were not entirely stable and resulted in detached cones. How- frameworks, it is possible to fabricate deformable solids by
ever, strict optimization of the fabrication parameters is neces- incorporating relatively crosslinked organic groups with a
sary to generate stable architectures. thin shell that can deform in the physiological environments
Although all the mesoporous solids that are successfully when encountered with high stress. In an attempt to explore
explored in diverse applications are highly stiff and hard in the deformable MSN solids, Teng et al. fabricated preferential-
nature; however, the reversible stiffness, in some instances, etching assisted PMOs based nanocapsules with intrinsically
plays a critical role in modulating the interactions of such flexible and deformable frameworks, that ­significantly offered
particles with the biological membranes, which could support an improved cellular internalization efficiency by deforming
their application in diagnosis and treating various ailments.[107] the overall morphology from the spherical-to-oval shape, which

Figure 15.  Multipodal and deformable MSN solids. A) TEM images of multipodal benzene–ethylene-bridged PMOs designed from the one-pot two
steps condensation process. Reproduced with permission.[97] Copyright 2015, Wiley-VCH. B) Plausible schematic showing the formation mechanism
of core-cone structured MSNs. Reproduced with permission.[106] Copyright 2015, Wiley-VCH. C) TEM images of thioether-bridged (a), benzene-bridged
(b), and ethane-bridged (c) mesostructured organosilica nanospheres synthesized via a CTAB directed sol–gel process. TEM images of thioether-
brdiged (a1,a2), benzene-bridged (b1,b2), and ethane-bridged (c1,c2) hollow PMOs (HPMO) nanocapsules prepared by etching the corresponding
organosilica nanospheres in a mild NaOH solution. Insets in (a2), (b2), and (c2) are the structural models of the deformed HPMO nanocapsules.
Reproduced with permission.[107] Copyright 2018, American Chemical Society.

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resulted in the enhancement by 26-fold over their solid coun- of such charged species. Several research groups have dem-
terparts (Figure  15C).[107] These innovative deformable, revers- onstrated this issue by using the additional design features,
ible constructs could open new burgeoning opportunities in such as coating of such small-sized MSNs (30–100  nm) with
nanomedicine. biocompatible polymers.[41] This approach is often practiced,
for instance, coating with a neutral polymer, PEG, which not
only augments the dispersion of particles in the suspension
4. Advances in the MSN Properties media but also provides steric hindrance in interfering with the
opsonization and concomitantly enhancing their circulating
4.1. Stability half-life and EPR efficiency. In addition, these neutral mole-
cules, in combination with the charged species, such as PEI,
The stability attribute of any formulation concerning its appli- can significantly augment the particle internalization character-
cability is a vital prerequisite as it plays a crucial role during the istics due to the electrostatic repulsions, thus maintaining the
development of nanocomposites for diverse applications.[108] adequate size of final formulation (Figure  16).[27] Despite the
Concerning the application of the nanoformulation, it is often excellent dispersibility of MSNs coated with polymers, it criti-
required to address various stability attributes, such as thermal, cally depends on the overall optimal surface charge of the final
colloidal, and hydrothermal stabilities, which predominantly composite that could result in the enhanced colloidal stability
depend on the composition of the respective nanoparticulate of the formulation.
forms. The colloidal stability of the particles often is contingent To the other end, the metal species that are encapsulated
on the structural firmness, which can be validated by the estab- in the confined nanospaces of MSN (namely, M-MSNs) could
lished intermolecular interactions among the individual parti- significantly augment the overall performance as well as the
cles as well as the surface of the particle and the surrounding thermal stability of the eventual construct owing to the excep-
molecules in the microenvironment. However, it should tional stability at high temperatures (>500  °C) favored by the
be noted that the formulations with poor colloidal stability transition metal species. These consequences could facilitate
results in the undesired reversible or irreversible aggregation their utilization as efficient catalysts for high-temperature reac-
depending on the interactions between the surfaces, leading to tions. However, the stability of MSNs mainly depends on the
the administration issues and inappropriate dosage frequen- silica precursor and the degree of oligomerization of silicate
cies. MSNs, are one such stable inorganic nanocontainers, have ions in them, in addition to the deposition of metal species at
gained enormous interest in drug delivery applications due an optimal ratio of silica to metal content, while at higher con-
to their robust thermal and colloidal stabilities, which could centrations than required may lead to the deposition of oxide
be acknowledged to their robust siliceous framework, overall forms and damage of the hexagonal channels of mesoporous
low density, and unique electronic architectures. However, in frameworks. Although the utilization of several transition metal
some instances, the colloidal stability of MSNs is altered due species in fabricating highly stable siliceous frameworks, a par-
to their tiny sizes, which, however, be influenced by the sur- ticular caution should be taken in regard to their colloidal sta-
rounding ionic conditions and proteins in the agglomeration bility and compatibility issues during biomedical applications

Figure 16.  Physicochemical characterization of different advanced MSNs. A) TEM images demonstrating the particle size and their dispersal in saline.
B) Photographs of the particles suspended in saline against an appropriate background were taken and supplemented with the illustrations to show
that NP3 coated with PEI–PEG had optical transparency because of electrostatic monodispersion. A,B) Reproduced with permission.[27] Copyright 2011,
American Chemical Society.

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as some of the metal species (Ca, and Mg, as well as some that the biological performance of MSNs is highly relevant to
first-transition-row metals, Fe and Cu) are available in trace the surface chemistries, and morphological attributes, con-
amounts in the body, which can perform the fundamental cerning the fabrication procedures and structural characteris-
enzyme cascade functionalities. In addition to the type of metal, tics of MSNs. In addition, these consequences are dependent
the concentration of such trace elements should be consider- on several other factors, such as type of cells, and concentra-
ably optimized while impregnating in the siliceous frameworks tion as well as the time of exposure of the formulation. Con-
for avoiding the toxicity issues. sequently, the surface-modified, small-sized MSNs resulted in
different distribution behavior in various vital organs, such as
spleen, liver, and lungs, compared to their counterparts, i.e.,
4.2. Biocompatibility and Safety naked large-sized MSNs, and eventually escaped from such
organs, resulting in the long-term circulation and slower deg-
In addition to the efficient delivery of therapeutic guest mole- radation as well as subsequent excretion rates. Apart from the
cules, the safety in terms of compatibility of any carrier-based surface chemistries, the morphology in terms of shape, i.e.,
formulation is the predominant concern to be considered for geometrical features, determine the organ distribution behavior
biomedical applications as this aspect significantly influences of MSNs. In one case, long rod-shaped MSNs that with high
the translation of such formulations from bench to bedside. aspect ratio resulted in higher accumulation in the spleen com-
Biocompatibility is generally practiced to comprehensively pared to the short rod-shaped MSNs and globular MSNs, which
explore the biological behavior of nanoparticles, exploring the were predominantly entrapped in the liver.[112] These conse-
induction of undesired responses in the body. Indeed, the sil- quences, explicitly demonstrated that the distribution of MSNs
ica-based materials are compatible and undoubtedly suitable for correlating to their safety is dependent on the various geomet-
utilization in vivo as silica is considered as “generally regarded rical and morphological attributes, after using various surface
as safe (GRAS)” material by the United States Food and Drug modification strategies. Although there exist numerous reports
Administration (US-FDA) and is one of the most abundantly on the safety issues of MSNs, it is evident from the literature
available endogenous constituents in the body.[3] In addition, it that there exist specific contrary findings on demonstrating
is often preferred in formulating oral dosage forms as a critical the effect of MSNs on tumor growth.[110] However, in-depth
bulk excipient for conveying therapeutic molecules through the analyses on establishing the comprehensive biological evalua-
gut. Considering the physicochemical characteristics, MSNs tion are required to precisely validate the physiological behavior
are one of such silica-based material species considered as of MSNs concerning the compatibility and safety issues along
high compatible delivery vehicles due to the morphological with the pharmacokinetic–pharmacodynamic (PK–PD) and
attributes and well-defined mesostructures.[109] Moreover, these dosing characteristics for better insight.
innovative porous materials are considerably safe and exhibit Due to their predominant administration route that sup-
altered biobehavior, for instance, low hemolytic effect, and posed to be the intravenous route, MSNs should be highly
excellent biodistribution along with accumulation efficiency in compatible with blood components, which could significantly
specific organs over the nonporous silica solids due to relatively determine its administration capability. Although the surface
low silanol density and well-defined mesostructured architec- is negatively charged, the hemolytic efficacy is comparatively
tures, i.e., high surface area and pore volume and large hydro- lower over the nonporous solids due to the reduced silanol den-
dynamic sizes facilitated by slight aggregation in physiological sity, which plays a crucial role in establishing the interactions
fluids, respectively. In addition to the morphological attributes, with the positively charged trimethylammonium groups in the
it is highly convincing from the chemistry point-of-view that RBCs of the blood. However, the administration route influ-
the surface functionalities possess extensive hydroxyl groups ences biological performance and other related safety issues. In
within the siliceous matrices, which could exceptionally liquefy a case, the subcutaneously administered MSNs exhibited excel-
under physiological environment resulting in the benign silicic lent biocompatibility over the intravenous- and intraperitoneal-
species. In this context, numerous reports indicated that the administered MSNs, which resulted in death due to the severe
MSNs exhibited low cytotoxicity in various cell lines cultured thrombosis.[111] As mentioned earlier, the surface modification
in vitro.[110] However, it should be noted that, in some instances, by PEG coating can further address these hemocompatibility
the remnants of ionic surfactants in the mesopores, while tra- issues. However, some of the reports based on the advanced
ditional chemical-based extraction, may lead to severe conse- MSNs were available, such as PMOs. For instance, the eth-
quences of toxicity. ylene-bridged MSNs have shown significantly higher hemo-
Contrarily, some investigations demonstrated that the pris- compatibility over the conventional MSNs. Further, to enhance
tine MSNs could themselves result in slight toxicity, which the accumulation of MSNs specifically in tumors, PEGylating
necessarily required the advancement of MSNs for their use in the MSNs, in combination with the positively charged polymers
biomedical applications. Furthermore, to augment the compat- like PEI, substantially enhanced the tumor uptake through the
ibility of traditional silica, several groups demonstrated specific EPR effect alongside overcoming the undesired biodistribution
improvements in altering the surface of MSNs (coating with and accumulation in major organs such as liver.[27]
the biocompatible polymers like PEG) by increasing the hydro- To this end, another type of advanced MSNs, i.e., metal-
philic functionalities over the surface, which could facilitate the incorporated MSNs have shown no visible toxic signs, exploring
augmented compatibility by reducing the opsonization through their safety concerns in various cell lines in vitro, for instance,
deprived nonspecific interactions with the biomolecules iron-encapsulated MSNs displayed excellent compatibility
in vivo.[111] These pieces of evidence significantly demonstrated in vitro, which could offer enormous potential in their utilization

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both in vitro and in vivo.[113] Notably, these pieces of evidence on however, the critical evaluation relevant to fundamental studies
the in vivo biocompatibility evaluations of MSNs have shown of such behavior and mechanisms involved are still in infancy.
that the behavior of various advanced MSNs is predominantly Moreover, the degradation of eventual MSN constructs expedi-
reliant on their various aspects of morphological attributes, sur- ently depends on the position of deposited metals in the MSN
face chemistries, and geometries, along with the dosage param- nanospace. For instance, the metals incorporated in the walls of
eters. The appropriate optimization of concentrations of metals silica through forming Si–O–M-based coordination interactions
in the mesoporous frameworks as well as altering surfaces to could facilitate the disassembly specifically in the acidic envi-
reduce the opsonization and undesired interactions with pro- ronment, i.e., stimuli-responsive degradation, while the metal
teins can efficiently facilitate the safety of advanced MSNs in species placed in pores, as well as the core of MSNs, could
applying them in vivo. follow the degradation behavior similar to traditional MSNs.
In addition, the stimuli-responsive degradation can support in
the degradation appropriately at the targeted site and substan-
4.3. Degradability tial elimination, ensuring no accumulation-induced biosafety
risk.[113] In a case, Omar and co-workers synthesized the iron
In addition to the surface chemistry involving the specific inter- oxide-containing biodegradable MSNs for protein (transferrin)-
actions, the degradability behavior in the biological fluids is mediated biodegradability (in only 3 days), which could offer
another prerequisite attribute that is explicitly correlated to the enormous potential for molecular-responsive drug delivery
biosafety of MSNs. Moreover, it plays a vital role in the elimi- application (Figure 17A).[115] Despite the structural integrity and
nation of the final composites after theranostic application in biocompatibility due to the advantageous morphological attrib-
vivo. This critical property has been under consideration in utes and surface engineering of these inorganic constructs, the
every modification or advancement of MSNs and focused well rapid degradation of advanced MSNs is a significant problem,
through a debate. Contrarily, poor degradation of such stable which often limits their applicability. In an attempt to address
inorganic nanocontainers would lead to the long-term accu- this issue, recently, we fabricated the dimetal (Cu and Fe)-doped
mulation in the body, posing to extreme side-effects, such as Janus-type, sphere-ellipsoid-shaped MSNs, in which the coordi-
thrombosis and undesired toxicity risks. Unlike the soft poly- nation interactions of metals within the siliceous frameworks
meric constructs, these nanoconstructs similar to the other relatively augmented the biodegradation behavior in the acidic
inorganic constructs, face a significant limitation of slow deg- environment (pH 5.0) over the PBS and serum at the pH values
radation ranging from several weeks to months due to their adjusted to 7.4 (Figure  17B).[73] The increased number of metal
structural integrity contributing to chemical, thermal, and species has significantly augmented the degradation of MSNs
mechanical stabilities.[114–116] It should be noted that the degra- through the disassembling of the coordination interactions
dation of silica materials often depends on various factors, such between the metals and siliceous frameworks. Interestingly, the
as chemical functionalities of the siliceous frameworks based degradation behavior was very rapid and completely degraded
on the type of surface engineering procedure, corresponding in 3 days compared to other reported Fe-doped samples, which
surface area and the influence of the surrounding dissolution took more than 6 days, and the presence of Fe in the sample
medium. More often, the silica materials prepared by the chem- was evident through the energy dispersive spectrometry (EDS)
ical extraction approach possess surface silanol groups with observations.[113] Although certain advancements have been
plenty of hydroxyl and alkyl groups over the high-temperature made, several obstacles remained to be explored, such as inves-
calcination approach, which could lead to the fast degradation tigations based on in situ demonstration of complex degrada-
in 2–3 weeks in the physiological fluids mimicking buffers. tion process in vivo and their substantial elimination from the
Moreover, the resultant degradation end-product of MSNs, i.e., body.
polysilicic acid species are nontoxic to various cell lines. On the
other hand, the highly porous architectures of MSNs with the
corresponding high surface area would provoke the degrada- 5. Initiatives and Scope for Clinical Translation
tion through the ease of infiltration of the buffers, which could
help them in heterogeneous degradation. In addition to struc- Although the significant number of studies relevant to fab-
tural stability, the components in the dissolution fluids influ- rication of diverse inorganic biomaterials and exploring the
ence the degradation behavior of the MSNs by forming specific biosafety and therapeutic efficiency in both in vitro as well as
salt complexed silicates over the silica surface, obstructing the in vivo are encouraging and convincing, the clinical translation
further degradation process and retaining its substantial frame- of such materials and their advanced prototypes has become
works intact.[117] highly challenging in the present scenario as there exists sig-
Interestingly, various modifications concerning advanced nificant gap between the fabrication procedures and the in vivo
MSNs have been proposed to increase the degradation behavior applications of MSNs. Apart from the therapeutic efficacy, the
of such MSNs, such as surface modification using organosi- comprehensive toxicity evaluation of MSNs is predominantly
lanes and incorporation of metal species in the frameworks. considered prior to the translation of any formulation from
Cauda et al. demonstrated the influence of various surface func- bench to the clinics, as the designed formulation is often dif-
tionalities, such as phenyl, chlorophenyl, and PEG, in which ferent from its counterparts in terms of various physicochemical
the phenyl group-immobilized MSNs degraded rapidly com- attributes.[17] In addition, several other aspects are considered,
pared to other functionalizations.[117] On the other hand, the such as resistance to degradation in the p ­ hysiological fluids, as
metal ions-doped MSNs also exhibited degradation behavior; they result in the undesired aggregation of the administered

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Figure 17.  Biodegradability of advanced MSNs for diverse applications. A-a) Schematic representation of the degradability of large-pore silica–iron
oxide nanoparticles in water and serum. Biodegradation of Fe-HMSNs, b,c) TEM images of the nanovectors before (b) and after (c) three days of
dispersion in water or d) in FBS. A) Reproduced with permission.[115] Copyright 2017, Elsevier. B) In vitro degradation of Cu–Fe MSNs in: a) media
with 10% serum, and phosphate-buffered saline (PBS), b) pH-7.4, and c) pH-5.0 (the inset box showing the optical images after centrifuging, left and
dispersion, right of the respective sample). d) Hydrodynamic sizes of Cu–Fe MSNs in media with 10% serum, and PBS at pH 7.4 as well as pH 5.0.
B) Reproduced with permission.[73] Copyright 2019, Elsevier.

nanoparticles leading to severe complications of thrombosis 6. Conclusions and Outlook

and eventually death. Despite the progress and success in the
fabrication and satisfactory biosafety prospects of silica, some In summary, we have highlighted and discussed the extensive
of the advanced prototypes have been subjected to the compre- research done on the fabrication of versatile advanced MSNs,
hensive biosafety evaluations both in vitro in various cell lines concerning their sizes, shapes, and physicochemical features,
as well as in vivo using animal models. in executing diverse functionalities. Efforts devoted to engi-
To this end, some of the critical examples from nanotech- neering MSNs with augmented physicochemical features, and
nological products of silica-based materials have been inves- morphological attributes have expanded their opportunities in
tigated in humans for their utilization in clinics. Although various applications for better performances both in vitro and
these studies are not under the scope of the review, we antici- in vivo. Regardless of the applications, the entire MSNs system
pate to discuss and update the view on a relevant topic for will enable the integrated realms of physics, chemistry, and bio-
better insight. For instance, the dye-doped silica-based C-dots medicine. Further, we emphasized the critical advancements
have been approved by US-FDA, showing enormous poten- made so far in engineering MSNs by improving physicochem-
tial toward cancer therapy and diagnosis. In another case, a ical attributes, ranging from the innovative chemistries for
nanomaterials-first-in-man (NANOM-FIM) clinical trial of the tuning the particle and pore sizes, surfaces, as well as siliceous
innovative bioengineered silica-AuNP-dispersed on-artery patch frameworks to fabricating various innovative and complex
was conducted in cardiac TE due to the high efficiency in car- architectures. We further emphasized the fabrication of MSNs,
rying therapeutic biomolecules and excellent biocompatibility focusing on the significant aspects of the scope of advance-
of silica-based materials.[118] The experimental results of athero- ments of MSNs in the context of structural and physicochem-
protective management have shown no appropriate toxicity ical attributes and their effects on biomedical applications.
signs and lower risk of cardiovascular death in humans with Despite the significant advancements in the fabrication
the nanoparticle-treated group.[119] However, some contrary and application of MSNs, several critical challenges persist
results in the same study stating that the Fe metal-immobilized regarding the processing, implementation, and subsequent
composites resulted in pronounced cytotoxicity and cardiac translation before commercialization, which made them far
health, which could limit its clinical advancement. Moreover, away from biomedical applicability. The production of MSNs
the critical optimization of the dosage of the formulation plays at an industrial scale hinges the scalability and batch-to-batch
a crucial role in the toxicity evaluation as the currently available reproducibility, which made them difficult to explore in the
techniques would limit the enumeration of PK–PD parameters bulk scale. Moreover, it is highly challenging to maintain the
and subsequent exploration of human models. Similar to the size uniformity as well as surface functionalization and loading
traditional MSNs, critical and systematic assessments should guest species and their ultimate collection in high yields. In
be made, and strengthening of the cooperation between the addition, the transformation of the product toward indus-
experts would lead to the enhancement of utilization scope trial production always results in an increase in cost, which
toward the translation of these innovative advanced prototypes is vastly different from the estimated and make them delayed
of MSNs, which could be available for utilization in clinics in in their adoption. As the clinical screening and application of
the future. the product generally require an industrial scale of production,

Adv. Mater. 2020, 1907035 1907035  (24 of 27) © 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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which is entirely different from the lab scale, it is highly neces- Foundation of Fujian Province (Grant No. 2019J01076), the support by
sary to develop various simplified and innovative strategies for the Fundamental Research Funds for the Central Universities (Grant
scale-up. To a considerable extent, some of these limitations can No. ZQN-713), Funds for Foreign Experts from the Ministry of Science
and Technology, China (Grant No. G20190013023), and Program
be fulfilled by developing cheap sources of silica and organic for Innovative Research Team in Science and Technology in Fujian
components required for functionalization, reduced steps of Province Universities. K.C.-W.W. appreciates the funding support from
production, timely processing, increased safety precautions by the Ministry of Science and Technology (MOST), Taiwan (109L891104).
establishing potential hazard regulations, among others. The Y.Y. is the recipient of Future Fellow (FT150100479), funded by the
available literature suggests that the current status is far away Australian Research Council (ARC). This work was performed in part
from practical applications. at the Queensland node of the Australian National Fabrication Facility,
a company established under the National Collaborative Research
Over the past two decades, there have been several advance-
Infrastructure Strategy to provide nano- and microfabrication facilities
ments in the fabrication of MSNs toward advanced prototypes for Australian researchers. Y.S.O. was supported by the Hydrogen Energy
and the substantial transformation of their evaluation from in Innovation Technology Development Program of the National Research
vitro to in vivo. However, the safety concerns of these advanced Foundation of Korea (NRF) funded by the Korean government (Ministry
MSNs remained incomplete. From the biologist’s point-of-view, of Science and ICT (MSIT)) (No. NRF-2019M3E6A1064197).
detailed investigations on safety and toxicity attributes at genetic,
biochemical, and epigenetic phases in the animal models,
including immunogenicity, neurotoxicity, and reproductive tox- Conflict of Interest
icity, of advanced MSNs, i.e., the surface as well as siliceous
frameworks modified MSNs, are required to be performed. The authors declare no conflict of interest.
Moreover, the fabrication protocols, morphological alterations,
surface modifications, and loading parameters can make sig-
nificant differences to the biosafety assessments. Although the Keywords
compatibility of the advanced MSNs is tested to some extent, it
mesoporous silica nanoparticles, metal shielding, nanomaterials,
still requires in-depth analyses both in vitro and in vivo. More- surface modification
over, there exists some information on their applicability in
vivo using some animal models and tissues, extensive investi- Received: October 27, 2019
gations relevant to the preclinical and clinical tests with MSNs Revised: February 23, 2020
in animals, and their exploration to humans yet remain to be Published online:
conducted. In this framework, for determining the biosafety in
vivo, various standard testing tools and procedures are required
to compare and assess the results from multiple platforms.
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