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Construction of Mesoporous Silica Based Smart Delivery System and its Therapeutic Application in Various Diseases

Qin Zhong , Shuai Zhou , Xiangmei Wang , Wei Zhong , Chendi Ding , Jiajun Fu

Progress in Chemistry ›› 2022, Vol. 34 ›› Issue (3) : 696 -716.

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Progress in Chemistry ›› 2022, Vol. 34 ›› Issue (3) : 696-716 DOI: 10.7536/PC210345
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Construction of Mesoporous Silica Based Smart Delivery System and its Therapeutic Application in Various Diseases
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Abstract

The drug delivery systems (DDSs) developed with advanced nanotechnologies can improve the physicochemical properties and therapeutic effects of drugs, while weakening their side effects. Therefore, nanoscale DDSs have become a hot spot and mainstream direction of current pharmacy research. Among them, mesoporous silica nanoparticles (MSNs) have the advantages of large specific surface area, adjustable morphology/structure, easy surface modification and good biocompatibility, thereby have attracted extensive attention of biomedical researchers and provided new design ideas for constructing new smart DDSs. In this paper, the latest research progress of MSNs-based smart delivery systems in construction and disease treatment applications is reviewed. Firstly, the development process, preparation methods and structural characteristics of MSNs are briefly summarized. Secondly, the construction strategies of MSNs-based smart delivery systems in recent years were systematically expounded from the perspectives of drug loading and gate-controlled release. The gatekeepers (such as polymers, inorganic nanoparticles, supramolecular assemblies and biomacromolecules, etc.) and controlled release mechanisms of various stimuli-responsive MSNs-based delivery systems were emphatically introduced. Afterwards, the applications of MSNs-based controlled release system in the treatment of various diseases (including cancer, bacterial infection, diabetes and Alzheimer's disease, etc.) was described in detail. Finally, the challenges in the investigations of MSNs-based smart nanocarriers are summarized, and the prospects of their future development are presented.

Contents

1 Introduction

2 Overview of mesoporous silica nanoparticles

3 Construction strategy of MSNs-based smart delivery systems

3.1 Drug loading strategies

3.2 Gated release strategies

4 Applications of MSNs-based smart delivery systems in disease treatment

4.1 Anticancer application of MSNs-based smart delivery systems

4.2 Antibacterial application of MSNs-based smart delivery systems

4.3 Application of MSNs-based smart delivery systems in diabetes treatment

4.4 Application of MSNs-based smart delivery systems in the treatment of other diseases

5 Conclusion and outlook

Graphical abstract

Keywords

mesoporous silica nanoparticles / stimuli-responsiveness / targeted delivery / drug loading / controlled release / disease treatment

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Qin Zhong, Shuai Zhou, Xiangmei Wang, Wei Zhong, Chendi Ding, Jiajun Fu. Construction of Mesoporous Silica Based Smart Delivery System and its Therapeutic Application in Various Diseases. Progress in Chemistry, 2022, 34(3): 696-716 DOI:10.7536/PC210345

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1 Introduction

In recent years, the rapid development of nano-biotechnology has promoted the development and application of drug delivery systems (DDSs), and the delivery technology based on DDSs is gradually changing the way of drug therapy[1,2]. Compared with traditional drug therapy, nano-DDSs (50 ~ 400 nm) can reduce the incidence of off-target effects, so that drugs mainly act on disease-related targets, thereby improving drug utilization and therapeutic effect. However, conventional DDSs still have some drawbacks, such as non-specific biodistribution in vivo and uncontrollable release mode, which make the therapeutic effect still poor and the toxic and side effects more significant. In order to overcome these drawbacks, researchers have developed intelligent stimulus-responsive DDSs with more clinical application prospects[3]. The intelligent nano DDSs can prevent the drug from leaking in advance in the delivery process, enrich the drug at the target tissue, realize the controlled release of the drug triggered by specific stimulation, maintain the effective blood concentration for a long time, and reduce the administration times, thereby significantly enhancing the drug effect and reducing the toxic and side effects. In the past two decades, researchers have developed many intelligent DDSs with diverse structures, forms and functions based on phospholipid molecules, polymers (including dendrimers, amphiphilic block copolymers, etc.), inorganic nanoparticles (such as graphene, quantum dots, Au, mesoporous silica, etc.) And other materials[4⇓⇓⇓⇓~9]. As a representative building block, mesoporous silica nanoparticles (MSNs) have attracted more and more attention in the field of drug delivery due to their large specific surface area, stable and tunable mesoporous structure, easy surface functionalization, strong loading capacity and good biocompatibility.
In the past decade, the research on mesoporous silica-based smart delivery systems has shown a vigorous development trend, which mainly aims at the efficient treatment of cancer. By modifying sensitive groups on the surface of mesoporous silicon, researchers constructed a tumor microenvironment/exogenous stimulus-responsive nano-drug carrier to ensure "zero release" of drugs before reaching tumor tissues, thus realizing the specific controlled release of drugs at tumor sites and greatly enhancing the selectivity, accuracy and effectiveness of cancer treatment. On the basis of optimizing the curative effect of cancer, the researchers also combined the intelligent drug delivery system with magnetic materials, fluorescent probes and other functional components to establish a multi-functional mesoporous silicon-based nano-diagnosis and treatment platform which integrates accurate diagnosis and targeted therapy[10⇓⇓~13]. With the further development of mesoporous silicon-based intelligent delivery system, the application of mesoporous silicon delivery system in the biomedical field is no longer limited to the diagnosis and treatment of cancer, but has expanded to the treatment of other types of diseases (such as bacterial infection and diabetes), and has achieved some meaningful results[14⇓⇓⇓~18]. It is worth noting that mesoporous silica has shown great potential in the field of biomedicine because of its large specific surface area, adjustable morphology, easy surface modification and strong loading capacity.However, with the development of research on mesoporous silica in recent years, it has also exposed some significant shortcomings in biomedical applications, such as poor biodegradability, long-term accumulation in the body, which may cause extremely serious side effects (such as thrombosis)[19]; There are some biological safety problems. It is reported that mesoporous silica materials can cause multiple organ toxicity, such as neurotoxicity, nephrotoxicity, lung toxicity, spleen toxicity, reproductive toxicity and immunotoxicity[20⇓~22]. These results indicate that the biological safety of mesoporous silica is questionable, and its toxicological properties should be revealed through a large number of in-depth in vitro and in vivo studies.
Based on the research status of mesoporous silica based smart nanocarriers, the development process, synthesis process and structural characteristics of mesoporous silica were briefly introduced in this paper. Secondly, the current construction strategies of mesoporous silica-based smart delivery systems are summarized from the aspects of drug loading and gated release, focusing on various stimuli-responsive mesoporous silicon gated switches (including polymers, inorganic nanoparticles, supramolecular assemblies and biomacromolecules) and their mechanisms of action. Then, the applications of mesoporous silica-based controlled-release systems in the treatment of various diseases, including cancer, bacterial infection, diabetes and Alzheimer's disease, are described in detail. Finally, the challenges in the study of mesoporous silica-based smart delivery systems are analyzed, and the future development prospects are prospected.

2 Overview of Mesoporous Silica Nanoparticles

Mesoporous silica nanoparticles (MSNs) are a class of silica materials with regular mesoporous structure (pore size of 2 ~ 50 nm). MSNs have been widely used in chemical engineering, environment, energy, biomedicine and many other fields because of their ordered and tunable pore structure, large specific surface area, controllable morphology and size, rich active silanol groups on the surface, high chemical/thermal/mechanical stability and good biocompatibility[23⇓⇓~26]. As early as 1968, St Stöber et al. Put tetraethyl orthosilicate (TEOS) into a mixed solvent of water and ethanol, and added ammonia as a catalyst to initiate the hydrolysis condensation reaction, and prepared monodisperse (uniform particle size) silica microspheres for the first time[27]. This method was later named St Stöber method, which laid the foundation for the subsequent preparation of MSNs. Until 1992, Beck et al. Of Mobil Company first synthesized MCM-41 mesoporous silica materials with ordered two-dimensional hexagonal pore structure by sol-gel method, using alkyl quaternary ammonium surfactant and silicate as structure-directing agent and silicon source, respectively[28]. This kind of mesoporous silica breaks through the pore size limitation of microporous materials (< 2 nm), and the size of regular pores is expanded to 2 ~ 10 nm. This landmark work has stimulated a wave of research on the design and synthesis of MSNs. In 1998, Zhao Dongyuan et al. pioneered the use of amphiphilic triblock copolymer Pluronic P123 (polyethylene oxide-polypropylene oxide-polyethylene oxide) as a structure-directing agent to prepare mesoporous silica materials (SBA-15) with a larger pore size range under acidic medium conditions[29]. SBA-15 mesoporous silica also has ordered two-dimensional hexagonal pore structure, and its pore size increases to 5 ~ 30 nm, and the thickness of pore wall can reach 6. 4 nm. Up To now, MSNs with various structures and morphologies have been prepared by sol-gel method using different types of surfactants (including anionic surfactants, cationic surfactants and nonionic surfactants) as structure-directing agents, including M41S series (MCM-41:MCM-48, MCM-50), SBA series (SBA-1, SBA-2, SBA-8, SBA-11, MBA-15, SBA16), AMS series (with anionic surfactants as templates), IBN series, and KIT series, etc. (Table 1). Among them, MCM-41 and SBA-15 are the most widely used mesoporous silica in the field of drug delivery.
The surfactant templating method based on sol-gel method is the most commonly used method for the synthesis of monodisperse mesoporous silica. The method utilizes surfactant molecules such as cetyltrimethylammonium chloride (CTAC) and cetyltrimethylammonium bromide (CTAB) as structure directing agents, and tetraethoxysilane (TEOS) or tetramethoxysilane (TMOS) as a silicon source. First, cationic surfactant molecules self-assemble into cylindrical micelles in alkaline medium, and then these micelles are arranged into ordered hexagonal close-packed structures. Then, silicon source TEOS/TMOS was added to make the hydrolysis and condensation reactions occur under alkaline conditions, forming electronegative silica subnanometer cores. These core particles grew along the micellar packing structure through the electrostatic interaction between ≡ Si — O — and —N+(CH3)3. And finally, removing the template agent in the particles by means of high-temperature calcination or chemical extraction and the like to obtain the mesoporous silicon nanoparticles with highly ordered pore structure. In the study of the synthesis of mesoporous silica, researchers have found that the morphology, size and mesoporous structure of the obtained mesoporous silica can be significantly changed by adjusting various reaction conditions and parameters, including template, raw material ratio, silicon source, pH value, reaction temperature and time, etc. For example, MSNs with different morphologies and micro-pore structures can be obtained by changing the types of surfactants. By changing the concentration of the silicon source in the reaction system, the number of crystal nuclei generated in the reaction can be changed, so that the size of MSNs can be adjusted; By changing the pH value of the reaction system, the hydrolysis rate and nucleation rate of the silicon source in the reaction were adjusted, and then the size of MSNs was changed. By changing the reaction temperature, the nucleation rate in the reaction will also be changed, causing the size of MSNs to change[30⇓~32].
For drug delivery applications, mesoporous silicon nanomaterials have several key intrinsic characteristics, including tunable size, morphology and structure, high specific surface area, easy surface functionalization, good biocompatibility and so on. The size of monodisperse MSNs can be adjusted from 7 nm to 300 nm, which is beneficial to the optimization of drug delivery efficiency. The pore size of MSNs is also adjustable (2 ~ 30 nm), so that MSNs can carry therapeutic agents of different sizes. Small-pore MSNs are generally used to load small molecule drugs, while large-pore MSNs can be used to encapsulate biomacromolecule drugs (such as genes and proteins). In addition, mesoporous silica has a high specific surface area (>700 m2/g) and a large pore volume (>1 cm3/g), which can achieve efficient loading of therapeutic agents. There are a large number of silanol groups distributed on the surface of MSNs, which can be covalently bonded to various forms of organic functional units and nanomaterials to meet the diverse needs of drug delivery applications. For example, the surface of MSNs can be modified with polyethylene glycol (PEG) to improve its water solubility and colloidal stability and prolong its blood circulation time in vivo[33]. In addition, mesoporous silicon materials can exhibit a variety of morphologies and structures, including nanospheres, nanorods, hollow nanospheres, rattle-shaped nanoparticles, Janus nanoparticles and core-shell nanostructures, which greatly enrich the functions of mesoporous silicon materials. Taking the typical core-shell nanomaterial Fe3O4@MSNs as an example, the system can simultaneously realize the functions of magnetic targeted drug delivery, magnetic resonance imaging and magnetic hyperthermia therapy[34]. More importantly, according to many literature reports, the results of in vitro toxicity tests of MSNs showed that MSNs had no significant toxic effects on a variety of normal cells and cancer cells, and the results of in vivo toxicity tests showed that MSNs did not cause significant histopathological changes[35,36]. It can be seen that mesoporous silica nanoparticles have great development prospects in the field of drug delivery as carrier materials.

3 Construction Strategy of Mesoporous Silica-based Smart Delivery System

3.1 Drug loading strategy

In 2001, Vallet-Regi et al. First used mesoporous silica nanoparticles (MCM-41) to carry drug molecules (ibuprofen) and successfully achieved drug release. Since then, the field of biomedicine has set off a wave of research on mesoporous silicon-based drug delivery systems[49]. Researchers have proposed a variety of feasible drug loading strategies, which can be roughly summarized into three categories: (1) pore drug loading, that is, the use of electrostatic interaction, physical adsorption and other non-covalent interaction to encapsulate drugs in the pores of MSNs; (2) surface drug loading, namely, the drug is connected to the surface of the MSNs in a covalent bonding mode; (3) Matrix drug loading, that is, drug incorporation into the silica matrix during the synthesis of MSNs (fig. 1). This subsection briefly describes these three drug loading strategies.
Pore loading is a simple and widely used loading strategy. The surface of the mesoporous silica particles is rich in silanol groups and shows electronegativity, so the water-soluble positively charged drug is easily adsorbed in the mesoporous channels to obtain the stably dispersed drug-loaded particles. For example, in 2018, Fang Chao's team physically mixed MSNs with doxorubicin (DOX) in phosphate (PBS) buffer solution to directly prepare a mesoporous silicon drug delivery system with high DOX loading (8.2%)[50]. In addition, the adsorption capacity of MSNs for drugs with different electrical properties can be improved by surface modification of ionizable groups such as carboxyl, amino and phosphate groups. Zhang et al. prepared strongly electropositive amino-functionalized MSNs, and efficiently adsorbed electronegative tirapramine (TPZ) and 5,6-dimethylflavone-4-acetic acid (DMXAA) into the mesoporous channels by electrostatic interaction (the loading amounts were 3.81% and 9.54%, respectively)[51]. A series of tests such as Zeta potential and elemental analysis proved that the two drugs had been successfully loaded into MSNs.
Abundant silanol groups make MSNs easy to be surface modified, so drug molecules with active groups (such as amino, carboxyl and sulfhydryl) at the end can also be coupled to the surface of MSNs by covalent bonding, that is, surface drug loading. For example, Du et al. Covalently coupled DOX to the pore walls of mesoporous silica using disulfide bonds (— SS —)[52]. The reaction of DOX with primary amine end group and bifunctional crosslinking agent N-succinimidyl-3- (2-pyridyldithio) propionate could form disulfide bonds to connect DOX with mercapto-modified MSNs, and the drug loading of MSNs-SS-DOX was 4. 2%. In addition, Zhao et al. Also used disulfide bonds to couple small interfering RNA (siRNA) to MSNs[53]. They modified the surface of mesoporous silicon with sulfhydryl groups, then functionalized MSNs with 2,2 '-dithiodipyridine, and then exchanged with sulfhydryl-modified siRNA to obtain disulfide bonds to connect siRNA with MSNs (MSNs-SS-siRNA).
Another drug loading strategy is skeleton loading, that is, additional drug molecules are added to the reaction system of MSNs, and with the formation of nanoparticles, the drug molecules are finally integrated into the whole silica skeleton. This strategy has attracted the attention of researchers because it is very simple to operate. For example, in 2019, Shan et al. Synthesized hollow mesoporous silicon nanoparticles (HMBRN) containing bilirubin (BR) by adding silanized bilirubin molecules in the process of synthesizing MSNs by sol-gel method, and then etching the silicon oxide spheres with ammonia in nitrogen atmosphere[54]. In addition, Qian et al. combined carbon nanodots (CDs) with hydrophilic polymers with cationic surfactant CTAB molecules through electrostatic/hydrogen bonding. Because CTAB combined with CDs self-assembled to form cylindrical micelles under alkaline conditions, silica particles grew along the micellar packing structure, so CDs could be integrated into the ordered mesoporous network structure of silica[55].

3.2 Gated release strategy

Although unmodified MSNs can achieve sustained release of loaded drugs to a certain extent through diffusion, these systems can not block the drug molecules in the pores, and the drug molecules are prone to leak under normal physiological conditions, causing damage to healthy tissues. In order to overcome the adverse effects caused by the early leakage of drugs, in 2008, Slowing et al summarized the previous experience and proposed the novel concept of gatekeeping, that is, using link molecules to anchor the gating elements such as inorganic nanoparticles, polymers and supramolecular assemblies to the surface of mesoporous silicon to seal the pores, so as to achieve the "zero release" characteristics under normal physiological environment[56]. Under the action of specific external stimuli (including endogenous stimuli such as pH, redox, enzyme and glucose, as well as exogenous stimuli such as light, heat, ultrasound and magnetic field), the structural transformation (such as decomposition, dissociation and isomerization) of the motif or the fragmentation of the linker triggers the controlled release of drugs. Gating motifs are the key components for the construction of stimuli-responsive DDSs. From the perspective of composition and structure, the gating motifs reported at present can be roughly divided into polymer gating, inorganic nanoparticle gating, supramolecular assembly gating and biomacromolecule gating[57]. In this section, the mesoporous silica delivery systems constructed by these gating motifs will be classified and described. In addition, the recent work of domestic researchers on the construction and application of mesoporous silica-based delivery systems (2019-2021) is shown in Table 2.

3.2.1 Polymer-Gated Mesoporous Silicon-based Smart Delivery System

Due to the diversity and easy modification of the polymer segment structure, the mesoporous silica delivery system using the polymer as the gating element can realize sensitive response to a variety of endogenous or exogenous stimuli to trigger the controlled release of drugs in the pores, and tightly seal the pores to prevent the early leakage of drugs under normal physiological conditions. In recent years, researchers have reported a variety of polymer gating motifs, which can be divided into three categories according to their structural forms, including polymer brushes, polymer networks and polymer coatings. These three types of polymer gating motifs are discussed separately below.
(1) Polymer brush gating: Polymer brushes are generally formed by initiating polymerization reactions in situ on the surface of mesoporous silicon (such as atom transfer radical polymerization (ATRP), reversible addition fragmentation chain transfer radical polymerization (RAFT), etc.) Or by high-density grafting of prepared polymer molecular chains onto the surface of mesoporous silicon. External stimuli (such as pH and temperature) are used to induce the contraction-extension conformational transition of polymer molecular chains, so as to control the on-off state of pores and realize the controlled release function of drugs. For example, poly (dimethylaminoethyl methacrylate) (PDMAEMA) is hydrophobic under alkaline and neutral conditions, and is hydrophilic due to the protonation of the polymer chain of PDMAEMA in an acidic environment, resulting in a coiling-stretching transition in its conformation. Based on the hydrophilic-hydrophobic transition characteristics of PDMAEMA, Wang Guojie's team reported a drug controlled release system composed of PDMAEMA molecular brushes grafted on the surface of MSNs through ATRP reaction[68]. Under the neutral or alkaline condition, the PDMAEMA chain segment shrinks and almost no drug leakage occurs; However, in the slightly acidic environment, Rhodamine B was released from the pore due to the transition of PDMAEMA chain segment from contraction to extension. Yu et al. prepared poly (N-isopropylacrylamide) -poly (4- (benzyl acrylate) phenylboronic acid pinacol ester) copolymer (PNIPAM-PBAPAE) on the surface of MSNs by ATRP reaction[69]. Because the thermosensitive PNIPAM can reversibly change its contraction-extension conformational transition in aqueous solution with the change of temperature, the system can achieve drug loading at low temperature and seal the pores by increasing the temperature. The PBAPAE skeleton contains phenylboronic acid, which is sensitive to reactive oxygen species (ROS), and the phenylboronic acid unit is rapidly oxidized to hydrophilic acrylic acid under the stimulation of ROS, resulting in a stretching transition of the PBAPAE conformation and subsequent release of the encapsulated drug (Fig. 2).
(2) polymer crosslink network gating: that polymer crosslink network is mainly obtained by crosslinking the polymer brush on the surface of the mesoporous silicon through covalent bonding or non-covalent interaction. Compared with the pure polymer brush, the polymer cross-linked network has a more compact structure, which can significantly reduce the risk of early release of drugs. Upon exposure to a specific stimulus (e.g., pH, redox, etc.), the covalent/non-covalent bonds that initiate crosslinking are broken, resulting in the collapse of the crosslinked network, thereby opening the pores and releasing the loaded drug. For example, Sun et al. Used RAFT reaction to prepare the copolymer of acrylic acid polyethylene glycol monomethyl ether methyl ester and N, N '-cystamine dimethacrylamide (a crosslinking agent containing disulfide bonds) on the surface of MSNs as a polymer network gated drug controlled release system[70]. Disulfide bond cleavage and reconstruction can be controlled by reduction and oxidation reactions. In the presence of dithiothreitol (DTT), disulfide bond cleavage can load drugs into nanopores. After the oxidant is added, the disulfide bond can be reconstructed to seal the mesoporous channel, so the on/off switching of the MSNs nanopore can be controlled, and the release of DOX can be realized under the reducing condition. Zhou et al. Prepared poly (glycidyl methacrylate) -poly (dimethylaminoethyl methacrylate) (PGMA-b-PDMAEMA) on the surface of MSNs through two consecutive ATRP reactions, and further covalently coupled coumarin molecules with PGMA-b-PDMAEMA side groups through cis-aconityl bonds[71]. Under UV irradiation, the coumarin groups on the surface of MSNs undergo cycloaddition and photodimerization to block the mesoporous channels. However, under acidic conditions, the release of the drug in the channels was promoted due to the hydrolysis of the cis-aconityl group and the shedding of coumarin, which led to the de-crosslinking of the copolymer network.
(3) Gating of polymer coating layer: The polymer coating layer is formed by directly coating some polymer materials with good biocompatibility on the surface of mesoporous silicon through covalent or non-covalent interaction. Compared with the polymer brush and the polymer network, the interaction sites between the polymer coating layer and the surface of the mesoporous silicon are more abundant, the combination is closer, and the modification method is simpler. Under the action of external stimuli (such as pH, enzyme and the like), the coating layer is degraded or the binding force between the coating layer and the surface of the mesoporous silicon is destroyed, so that the coating layer and the surface of the mesoporous silicon are separated to expose a pore channel, and a carried drug is released. For example, in 2019, Peng et al. Used acid-sensitive imine bonds to coat polyethylene glycol methyl methacrylate-polymethacryloylethoxybenzaldehyde copolymer (PEGMA-PMAEBA) on the surface of MSNs to obtain a pH-responsive drug controlled release system[72]. In an acidic environment (pH = 5.0), the imine bond was cleaved, and the copolymer coating layer was detached from the surface of MSNs, followed by the release of DOX. In addition, Lin et al. Modified chitosan with dendrimer polyamide (PAMAM) by click chemical reaction, and then connected the cationic polymer-modified chitosan to the surface of MSNs by disulfide bonds to block DOX in the pores[73]. Under reducing conditions, the disulfide bond was cleaved, the chitosan derivative was detached from the surface of MSNs, and DOX was released.

3.2.2 Mesoporous Silica-Based Smart Delivery System Gated by Inorganic Nanoparticles

Inorganic nanoparticles are also widely used as gating units in mesoporous silica delivery systems due to their simple preparation, regular morphology, adjustable size and easy surface modification. Inorganic nanoparticle-gated mesoporous silica smart delivery systems are usually constructed by attaching small inorganic nanoparticles (< 10 nm) to the surface of mesoporous silica using environmentally sensitive groups, and the pores are tightly blocked by inorganic nanoparticles, so these delivery systems can ensure zero release of drugs under normal physiological conditions. At the same time, due to the stimuli-responsiveness of the linking group, this kind of system can realize the controlled release of drugs under specific stimulation.
Quantum dots (2 ~ 10 nm) are generally composed of semiconductor materials, such as ZnS, CdS and CdSe. As a typical representative of small-sized inorganic nanomaterials, it has the advantages of high specific surface area and easy surface modification, and shows good fluorescence characteristics. Fluorescent quantum-dot-gated mesoporous silica smart delivery systems based on quantum dots (QDs) as gating motifs, which can achieve controlled drug release and real-time monitoring of the delivery process, have attracted wide attention in the biomedical field. For example, Knezevi Knezević et al. realized the stimulus-responsive release of anticancer drug camptothecin (CPT) in magnetic mesoporous silica (MMSN) by using CdS quantum dots as gating motifs[74]. They synthesized magnetic mesoporous silica embedded with magnetic nanoparticles (Fe3O4) by co-condensation sol-gel method, and then connected 2-nitro-5-mercaptobenzyl alcohol-functionalized CdS on the surface of MMSN through o-nitrophenylcarbamate bond to block the pore entrance. Under UV irradiation, the o-nitrophenyl carbamate bond was photocleaved, and the CdS particles were detached from the surface of the material, thus triggering the release of CPT molecules. However, because these semiconductor quantum dots contain heavy metals and are not biodegradable, their application has potential biological toxicity risks. Compared with traditional semiconductor quantum dots, carbon-based quantum dots (including carbon quantum dots and graphene quantum dots) show higher biocompatibility and lower toxic side effects, which make them more potential for clinical application. A pH-responsive drug delivery system was constructed by coupling graphene quantum dots (GQDs) with acetal bonds on the surface of MSNs[75]. Under neutral conditions, GQDs can seal the nanopore and block the leakage of guest molecules from the orifice. When exposed to an acidic environment, the GQDs nanocaps fall off due to hydrolysis of the acetal bond, thereby releasing the encapsulated drug. GQDs can not only act as blocking elements of controlled release systems, but also monitor the drug delivery process by their own fluorescence effect. Zhu Junjie's team used a similar strategy to cover GQDs at the pore entrance of MSNs to prepare fluorescent mesoporous silicon nanoparticles (FMSNs) that can monitor drug delivery in real time[76]. They prepared FMSNs-FA by grafting ATP aptamer (FA) on the surface of amino-modified MSNs through amidation reaction. FMSNs-FA efficiently adsorbs GQDs via π-π stacking to seal the nanopores of FMSNs. At low ATP levels (< 0.4 mmol/L), GQDs blocked the pore entrance to prevent drug leakage; However, in the environment of high concentration of ATP (1 ~ 10 mmol/L), GQDs were shed, resulting in the release of encapsulated drug molecules. Due to the fluorescent properties of GQDs, the nanocarrier can also be used for real-time monitoring of drug delivery.
Noble metal nanoparticles, such as gold nanoparticles (AuNPs), have become the most widely used metal materials in the biomedical field due to their high biocompatibility, morphology and size tunability, and unique optical properties. In addition, the superior properties of noble metal nanoparticles, such as high specific surface area and easy surface modification, make them ideal gating motifs for mesoporous silica delivery systems. Similar to the establishment of quantum dot gating, researchers generally use stimuli-responsive groups to connect noble metal nanoparticles to the surface of mesoporous silicon to block the entrance of pores and achieve effective regulation of drug release behavior. For example, Liu et al. First used AuNPs to block the pores of mesoporous silicon to establish an acid-sensitive drug controlled release system[77]. Acetal modified MSNs were coupled with carboxyl modified AuNPs by amidation reaction, thus the AuNPs were grafted on the surface of MSNs to block the pore entrance. Under acidic conditions, the hydrolysis of the acetal bond leads to the shedding of the gold nanocap, so that the encapsulated drug molecules escape from the pore in a controlled manner (fig. 3). Mesoporous silica-based DDSs with silver nanoparticles as gating units have also been reported. For example, Tan Weihong's team prepared a new nano-carrier AuNR @ MSNs @ AgNPs with AgNPs as the nano-cap, gold nanorods as the core and mesoporous silicon as the shell[78]. The as-prepared AuNR @ MSNs were first carboxylated, and then functionalized with Ag+ specific DNA single strand (P1), followed by in situ formation of AgNPs by reduction of Ag+ with NaBH4 to plug the silica channels. In the reducing environment, the AgNPs nanocaps were detached due to the breakage of the Ag-S bond, and the encapsulated drug molecules were also released.
In addition to the above two types of typical inorganic nanoparticles, magnetic nanoparticles have also attracted wide attention in the field of nanomedicine because of their unique magnetic field responsiveness. Magnetic nanoparticles, as the gating unit of mesoporous silica controlled release system, can realize the directional and fixed-point control of drug release, which has great application prospects in the field of biomedicine. For example, Giri et al. anchored magnetic nanoparticles Fe3O4 on the surface of mesoporous silica, and constructed mesoporous silica-based nanocarriers with Fe3O4 as gating[79]. They attached the amino-modified Fe3O4 to the surface of 3- (propyldisulfide) propanoic acid-functionalized MSNs (Fe3O4-SS-MSNs) by amidation reaction. When the system is under reducing conditions, the disulfide bonds are cleaved and the encapsulated drug is released. In addition, the use of external magnetic fields can guide the directional transport of magnetic Fe3O4-SS-MSNs and enhance their ability to be taken up by cells. Gan et al. anchored boric acid-functionalized Fe3O4 on the surface of MSNs through a reversible borate ester bond to obtain an acid-sensitive magnetic mesoporous silica-based drug carrier[80]. In a neutral environment, Fe3O4 nanoparticles effectively seal the nanopores of MSNs and prevent drug molecules from escaping from the pores. However, under acidic conditions (pH 2 to 4), the Fe3O4 nanoparticles were detached from the surface due to the cleavage of the borate ester bond, resulting in rapid release of the drug from the MSNs. In addition, the carrier has the physical targeting capability of magnetic mediation, so that the specific release of the drug can be realized at the target tissue[81].

3.2.3 Mesoporous Silicon-based Smart Delivery System Gated by Supramolecular Assembly

In recent years, molecular recognition and self-assembly based on macrocyclic receptors have become an important part of supramolecular chemistry. Cyclodextrins, fullerenes and cucurbiturils are common macrocyclic acceptors with important application value.These macrocyclic acceptors can form molecular machines with unique topological structures through supramolecular self-assembly with some molecular bearing compounds with special functions, such as rotaxanes, pseudorotaxanes and polyrotaxanes[82]. Molecular machines can dynamically sense external stimulus signals, which change the force between the molecular bearing axis and the macrocyclic receptor, and then trigger the corresponding molecular state transformation, that is, chain movement. Inspired by this, Zink and Stoddart first proposed the concept of Nanovalve based on supramolecular assembly in 2004.That is to say, the molecular bearing is anchored on the surface of the carrier and the macrocyclic receptor is enveloped by the supramolecular force (such as hydrophobic interaction and Van der Waals force) to form a supramolecular assembly to block the nanopore of the carrier, thus constructing an intelligent response drug controlled release system[83]. Mesoporous silicon is the most commonly used material as drug carriers in nano-valve systems, and many researchers have successfully established various forms of responsive molecular machines on its surface. Among them, scientists represented by Zink and Stoddart have done a lot of pioneering research in this field from 2004 to 2010, and fully demonstrated the response release function of supramolecular nano-valve-mesoporous silicon system from the theoretical and experimental point of view[84⇓⇓~87].
Cyclodextrins (CDs) are a class of cyclic oligosaccharides derived from the degradation of starch by cyclodextrin glycosyltransferases. They are composed of D-glucopyranose units linked by α-1,4-glycosidic bonds from beginning to end. According to the number of glucose units, CDs can be divided into α- (6), β- (7) and γ-CDs (8)[88]. Cyclodextrins have both a hydrophobic cavity and a hydrophilic outer wall, and the cavity can include hydrophobic guest molecules with matching size, so they can be used as drug excipients and carriers for drug modification and sustained release. In the past decade, cyclodextrins, as the second generation of macrocyclic receptors, have been widely used to construct mesoporous silica-based smart delivery systems gated by supramolecular assemblies due to their excellent molecular bonding ability. For example, Liu et al. constructed a poly-β-cyclodextrin (PCD) gated mesoporous silicon nano-delivery platform by using host-guest interaction[89]. They first modified the surface of MSNs to connect disulfide pyridine groups, and then added PCD to complex with pyridine through host-guest interaction. Under reducing conditions, the disulfide bond was cleaved and the PCD-pyridine supramolecular assembly was detached from the surface of MSNs, triggering the release of DOX. When the pyridine group was protonated by tertiary amine under acidic conditions, the complexation between PCD and pyridine was weakened, and the detachment of PCD from the surface of MSNs also promoted the release of DOX from the channels. Our group has also done related work, we use the acid-sensitive hydrazone bond to connect hydrazinomethylene azobenzene (HMAB) to the surface of aldehyde modified mesoporous silicon, and then use α-cyclodextrin (α-CD) molecules to include the azobenzene group, forming a mesoporous silicon nano-carrier with α-CD as the capping agent[90]. Under acidic conditions, the release of DOX was triggered by the dissociation of α-CD from MSNs due to the hydrolysis of the hydrazone bond. Under UV irradiation, the affinity between azobenzene and α-CD was weakened due to the change of azobenzene group from trans conformation to cis conformation, and α-CD molecules were detached from the surface of MSNs, and DOX was released (Fig. 4).
Pillar arenes are a class of cylindrical macrocyclic acceptors consisting of 1,4-dimethoxybenzene rings connected by methylene bridges. Since it was reported in 2008, as a new generation of macrocyclic receptors, pillar arenes have been favored by many researchers, and the supramolecular chemistry based on pillar arenes has made considerable progress[91]. Due to its highly rigid columnar skeleton, electron-rich hydrophobic inner cavity and strong host-guest properties, pillararenes can construct new assemblies containing different guest molecules, so pillararenes have important research significance and application value in many fields, including drug delivery. In recent years, mesoporous silica controlled release systems based on pillared arene gating have been widely studied and reported. For example, in 2016, our group constructed a mesoporous silica controlled release system gated by water-soluble carboxylated pillarene (WP5)[92]. A kind of bistable pseudorotaxane was anchored on the surface of mesoporous silica.Its molecular axis was supported by 1- (6-aminohexyl) -pyridine (APy) and 1,6-hexanediamine (HDA) as two binding sites, which formed a supramolecular valve with WP5 to seal the mesoporous silicon channels. The system was designed according to the different binding abilities of WP5 with APy and HDA, and the binding constant (K=1.29×106L/mol) of WP5 with HDA was significantly larger than that (K=1.21×104L/mol) under neutral conditions, so WP5 first bound to the HDA site close to the surface of mesoporous silica, and the valve was closed to bind rhodamine B in the pore. However, under alkaline condition, the deprotonation of HDA leads to the decrease of the interaction between WP5 and HDA, which makes WP5 migrate to the APy site far away from the surface of mesoporous silica, and Rhodamine B is released. When in an acidic environment, the water solubility of the protonated WP5 of the terminal carboxyl group is reduced, and the WP5 falls off from the molecular bearing shaft, so that the rhodamine B is released; In the environment rich in Zn2+, the carboxyl group at the end of WP5 chelates with Zn2+, which makes WP5 dissociate from the surface of mesoporous silica and open the nano-valve. Therefore, the system can simultaneously respond to triple stimulation of acid, alkali, Zn2+ and the like to realize the controlled release of the drug. Subsequently, Du Xuezhong's team designed a mesoporous silicon-based intelligent delivery system gated by water-soluble phosphonated pillarene (PPA [5])[93]. PPA [5] binds to quaternary ammonium salts or pyridinium cations on the surface of MSNs through electrostatic interaction to achieve responsive drug release driven by acidic pH, Zn2+ and competitive binding agent methyl viologen (MV). In 2019, Yang Yingwei and others constructed magnetic mesoporous silicon delivery materials gated by supramolecular valves[94]. They connected the magnetic nanoparticles Fe3O4(WP[5]A-Fe3O4) with carboxylated pillarene on the surface to the surface of pyridine-functionalized mesoporous silicon through inclusion. Under the stimulation of acid/base, competitive binder 1,4-butanediamine (BDA) and ultrasound, the binding force between WP[5]A-Fe3O4 and pyridine was weakened, so it fell off from the surface of the material and released the encapsulated drug. In addition, the system has magnetic targeting properties due to its inclusion of superparamagnetic Fe3O4.

3.2.4 Mesoporous Silica-Based Smart Delivery System Gated by Biomacromolecules

Biomacromolecules (including nucleic acids, carbohydrates, peptides and proteins) can effectively overcome the adverse effects (such as immune response, difficult degradation and long-term toxicity) caused by inorganic nanoparticles, polymers and other materials, and biomacromolecules show some unique properties due to their special structures.For example, the transition of conformation or state under external stimulation, the close complexation with ligand small molecules, etc. Therefore, the construction of stimuli-responsive mesoporous silica controlled release system using biomacromolecules as a new generation of gating materials has become one of the current research hotspots in the field of drug delivery.
Deoxyribonucleic acid (DNA) molecules have shown great potential in the field of drug delivery due to their high biocompatibility, stability and structural programmability. Through precise and controllable structural design, DNA molecules, as the gating elements of the controlled release system, can undergo structural or conformational changes under external stimuli such as pH, enzyme and temperature, so that drugs can be released from the pores, thus achieving precise drug delivery and reducing toxic and side effects. For example, Zhu et al. developed magnetic mesoporous silica nanocarriers gated by DNA duplex molecules[95]. They embedded Fe3O4 nanoparticles in the framework of mesoporous silicon to form magnetic mesoporous silicon (MMS), then coupled 6- (maleimido) hexanoic acid succinimidyl ester (sulfo-EMCS) with amino-modified MMS, and then single-stranded DNA (ssDNA) was connected to the surface of MMS through click chemistry reaction. After loading DOX, cDNA with complementary bases was hybridized with ssDNA through hydrogen bonding to form double-stranded DNA (dsDNA) to close the mesoporous channel. Under the action of alternating magnetic field, magnetic Fe3O4 nanoparticles generated high heat, which led to the complete dissociation of DNA double strands and the release of loaded DOX (Fig. 5). In addition, Zhang et al. reported a QD-embedded mesoporous silica delivery system (MSQDs) with DNA hybrid as a blocking agent[96]. They modified the anchor DNA chain (anchor-DNA) on the surface of MSQDs through amidation reaction, and then combined the DNA hybrid assembled by DNA aptamer (AS1411) and antisense oligonucleotide (anti-miR-21) with the anchor DNA through hydrogen bonding, thus sealing the mesoporous silicon channel and preventing the premature leakage of drugs. When miR-21 molecules are present in the environment, miR-21 competes to bind to the anchor DNA strand, causing the DNA hybrid to detach from the surface of MSQDs, thereby releasing the drug.
Peptides and proteins are important functional macromolecules that are ubiquitous in organisms and involved in the regulation of almost all life processes. Compared with synthetic polymers, inorganic nanoparticles and other conventional carrier building elements, peptides and proteins, as new carrier building materials, have a series of advantages, such as low immunogenicity, degradable metabolism, easy targeted modification and inherent biological activity.Therefore, it is widely used in the field of drug delivery and provides a new design idea for the development of mesoporous silicon intelligent delivery system. A new generation of mesoporous silica-based intelligent controlled release system can be constructed by using peptides and proteins as responsive gating elements. For example, Zhang Xianzheng's group reported a matrix metalloproteinase-2 (MMP-2) enzyme-responsive fluorescent peptide (MFIP) gated mesoporous silica nanocarrier[97]. The azide-terminated MFIP is composed of an MMP-2 substrate peptide PLGVR, a fluorescent dye 5 (6) -carboxytetramethylrhodamine, and a quencher 4-dimethylamino-4 '-methylazobenzene. They used click chemistry to connect MFIP to the surface of mesoporous silicon modified by alkynes, thus sealing the mesoporous channels. When the carrier is in the environment of high concentration of MMP-2, the substrate peptide PLGVR is hydrolyzed, MFIP is detached from the surface of the carrier, and the drug is released from the pore channel. In addition, Lu Guangming's team covered the surface of mesoporous silicon with natural non-toxic positively charged cytochrome C (Cyt C), and constructed a protein-gated pH-responsive mesoporous silicon-based delivery system[98]. Under neutral conditions (pH = 7. 4), positively charged Cyt C can be adsorbed on the surface of negatively charged mesoporous silica by electrostatic interaction, sealing the mesoporous pores. When the system is in an acidic environment (pH = 5.5), the hydroxyl groups on the surface of the mesoporous silicon are protonated, and the Zeta potential changes from negative to positive, so that electrostatic repulsion occurs between the hydroxyl groups and Cyt C, Cyt C falls off from the surface of the mesoporous silicon, and the drug DOX is released.

3.2.5 Other Types of Gated Mesoporous Silicon-based Smart Delivery System

In addition to the common gating materials described above, some special forms of gating elements have also been reported. A simple and efficient stimuli-responsive mesoporous silica-based drug delivery carrier can be constructed by coating a layer of degradable inorganic nanoshells (such as calcium carbonate, calcium phosphate, etc.) On the surface of mesoporous silica in situ. For example, Guo Shanming's group prepared a mesoporous silica nanocarrier gated by calcium carbonate layer by water-in-oil (w/o) microemulsion method[99]. They first coated the surface of mesoporous silicon with calcium carbonate layer, and then coated the nanocarrier with cancer cell membrane (CM). The release of DOX was triggered by the dissolution of the calcium carbonate layer when the carrier was exposed to acidic conditions. In addition, in view of the complex preparation process and poor response sensitivity of the traditional gated switch mesoporous silicon delivery system, some researchers have established a stimuli-responsive drug self-gated nano-delivery system by using sensitive covalent bonds to directly immobilize bioactive drugs on the surface of mesoporous silicon, making the drugs themselves act as gated switches. For example, Zeng et al. First synthesized a mesoporous silica controlled release system with self-gating of drug molecules[100]. They first functionalized MSNs with benzaldehyde, and then directly encapsulated DOX, an anticancer drug, to form a pH-sensitive benzylimine bond through the reaction of the terminal amino group of DOX with benzaldehyde, so that DOX itself was used as a gating motif to obtain a pH-sensitive self-gated drug delivery system. When the system is in a weak acidic environment (pH = 6.8), the benzylimine bond is hydrolyzed, the nano-valve is opened, and the DOX in the pore is released (Fig. 6).

4 Application of Mesoporous Silica Based Smart Delivery System in Disease Therapy

4.1 Anticancer Application of Mesoporous Silicon-based Smart Delivery System

Malignant tumor is one of the major diseases that seriously threaten human health and life, and the number of new cases and deaths has increased significantly year by year. According to the statistical analysis of the International Agency for Research on Cancer, there were 18.1 million new cancer cases and 9.6 million new deaths worldwide in 2018[101]. At present, surgery, chemotherapy and radiotherapy are the most commonly used clinical treatment of cancer, but these traditional treatments still have many defects, including non-specific treatment, easy metastasis and recurrence, multi-drug resistance and serious side effects. With the development and rise of nano-drugs, the drawbacks of traditional cancer treatment technology are expected to be overcome. Through the enhanced permeability and retention (EPR) effect of solid tumors or surface coupling with targeted ligand molecules, nano-drug carriers can achieve selective drug delivery to tumor tissues in a passive or active targeting manner, thereby improving the bioavailability of anticancer drugs, enhancing the therapeutic effect and reducing the toxic and side effects. In addition, the loss of control of cell transformation and growth in tumor tissues leads to hypoxia in the tumor microenvironment and abnormal metabolism of cells, so that tumor tissues show significantly different physiological characteristics from normal tissues, including: (1) the hypoxic tumor microenvironment is slightly acidic (pH 6.5 ~ 6.8);(2) high concentration of glutathione (GSH) in tumor cells (2 ~ 10 mmol/L), (3) high concentration of ROS in tumor cells, such as hydrogen peroxide, hydroxyl radical and superoxide, etc. (4) Tumor cells highly express a variety of enzymes, such as matrix metalloproteinase (MMP), hyaluronidase and telomerase. (5) Tumor cells express specific antigens or antibodies (such as CD19, HEK2, etc.)[102]. Based on these characteristic pathological signals, in recent years, researchers have constructed many mesoporous silica-based controlled-release carriers responsive to tumor microenvironment, which have structural or conformational changes in blocking elements under specific endogenous stimuli such as pH, GSH and enzymes.So as to trigger the precise and controllable release of the carried drugs (including small molecular drugs, genes, polypeptides and other active macromolecules), and achieve fixed-point and quantitative drug delivery and higher therapeutic effect. For example, Cai Kaiyong's team connected the bifunctional composite peptide composed of cell penetrating peptide (CCP) and MMP-2 substrate peptide to the surface of carboxyl-modified mesoporous silicon through amidation reaction.A tumor-specific enzyme-sensitive mesoporous silica targeted drug delivery system was prepared by covalently bonding the human serum albumin-phenylboronic acid conjugate (HAS-PBA) as a pore-blocking agent with the surface complex peptide through an amide bond[103]. Due to the high affinity of PBA for sialic acid on the surface of HepG2 cells, the mesoporous silica delivery system can selectively accumulate in the liver tumor site, and then the high concentration of MMP-2 in the tumor microenvironment specifically degrades the MMP-2 substrate peptide. The exposed CPP promotes the uptake of cancer cells into the delivery system, and a large amount of doxorubicin is released intracellularly due to the removal of the blocking agent. The results of in vitro and in vivo experiments show that the delivery system can efficiently induce apoptosis and inhibit tumor growth, and reduce the toxic and side effects on normal tissues. In addition, Sun et al. Attached positively charged polyethyleneimine (PEI) to the surface of negatively charged mesoporous silicon and crosslinked the PEI coating with a crosslinking agent, dithiobis (succinimidyl propionate), to construct a mesoporous silicon nanocarrier gated by a polymer network formed by reversible disulfide crosslinking for the delivery of vascular endothelial growth factor small interfering RNA (VEGF siRNA) in cancer cells[104]. After the siRNA-loaded nanoparticles were internalized by KB cells, the high concentration of intracellular GSH triggered the controlled release of siRNA and down-regulated the expression of vascular endothelial growth factor, thus inhibiting angiogenesis and promoting vascular normalization, and ultimately slowing down tumor growth. The results of in vivo experiments showed that the inhibition rate of VEGF expression was 46%, and the inhibition rate of tumor growth was about 40%, showing a good tumor treatment effect.
Malignant tumors exhibit unique heterogeneity and complexity of pathogenesis, and tumor cells develop multidrug resistance as therapy progresses, which makes it impossible to treat cancer effectively with single therapeutic agents. Therefore, combination therapy involving multiple anticancer drugs has become an increasingly important treatment. Combination drug delivery system has become one of the most popular directions in current anticancer research. Anticancer drugs with different mechanisms of action produce synergistic effects, effectively inhibit the formation of tumor multidrug resistance, and achieve efficient treatment of cancer. For example, Cheng et al. reported a pH-responsive mesoporous silica carrier for targeted delivery of small molecule drugs and genes, which uses DOX as an acid-sensitive gating motif to block P-glycoprotein small interfering RNA (P-gp siRNA) loaded in the pore[105]. The acid environment in the tumor cell breaks the benzylimino bond between the DOX and the surface of the mesoporous silicon, so that the synchronous release of the siRNA and the DOX is realized. Western blot (WB) results showed that siRNA could effectively inhibit the expression of P-gp protein in MCF-7/ADR, prevent drug efflux, and reverse multidrug resistance. The results of in vitro and in vivo experiments showed that the co-delivery system could produce synergistic anticancer effect and inhibit the proliferation of drug-resistant tumor cells (IC50 was as low as 5. 48 μg/L, tumor growth inhibition rate was about 78%). In addition, the co-delivery of anticancer drugs and therapeutic peptides or proteins is also a potential therapeutic strategy to effectively inhibit tumors.Xiao et al. constructed a GSH-sensitive mesoporous silica co-delivery system (DOX @ TTSTMSN) using therapeutic peptides containing RGD sequences ( (RGDWW)2KC) linked to the surface of mesoporous silica through disulfide bonds[106]. Because the branched therapeutic peptide contains abundant tryptophan units, they utilized π-π stacking and hydrophobic interactions to achieve efficient loading of DOX. Through integrin-mediated endocytosis, the nanocarrier was taken up by U-87MG cells in large quantities, and GSH triggered the combined delivery of DOX and therapeutic peptides after entering the intracellular reducing environment. Similar to the function of DOX, therapeutic peptides containing RGD motifs also act on intracellular nucleic acids through strong π-π stacking, thereby inducing apoptosis. The results of in vivo experiments using hepatocellular carcinoma xenograft model showed that the combination of DOX and therapeutic peptide had a significant synergistic inhibitory effect on tumor growth, and the results of hematoxylin and eosin (H & E) staining also showed that the system had a serious killing effect on cancer cells.
With the further development of cancer treatment research, scientists have developed a variety of new cancer treatment modalities besides chemotherapy, radiotherapy (RT) and gene therapy in recent years, such as photothermal therapy (PTT), photodynamic therapy (PDT), sonodynamic therapy (SDT) and chemokine therapy (CDT). The combination of chemotherapy/gene therapy mediated by mesoporous silicon-based intelligent delivery system with these advanced treatment modes can further enhance the tumor suppression effect and even achieve the complete eradication of tumors. This innovative modular design strategy has been adopted and applied by many biomedical researchers. For example, Zhu et al. assembled a stimuli-responsive chemotherapy-photothermal combination therapy nanoplatform by using a Passerini reaction near-infrared absorption dye BODIPY, an aldehyde-terminated polyethylene glycol (PEG-CHO), and a disulfide carboxyl-modified mesoporous silica[107]. The high concentration of GSH in cancer cells triggers the release of DOX on demand.Under the irradiation of 638 nm red light, the system produces a significant photothermal effect (photothermal conversion efficiency of about 36. 7%), thus realizing the dual synergistic treatment of photothermal therapy and chemotherapy for tumors. The results of in vitro and in vivo experiments showed that the nano-platform had obvious synergistic effect of chemotherapy and photothermal enhancement. Through layer-by-layer assembly strategy, Yang et al. coated multiple layers of alginic acid and chitosan alternately on the surface of amino-modified magnetic mesoporous silicon for loading anticancer drug DOX, photosensitizer chlorin E6 (Ce6) and P-gp shRNA, and constructed a pH-responsive magnetic targeted mesoporous silicon nanosystem with chemotherapy, gene therapy and photodynamic therapy functions[108]. After the system was taken up by cancer cells, the weak acidic environment of the endosome triggered the swelling of the dense polyelectrolyte layer, which promoted the release of DOX and Ce6 from the carrier, and the loaded shRNA overcame multidrug resistance. Meanwhile, under the irradiation of red light at 660 nm, Ce6 produced a large amount of cytotoxic singlet oxygen. Therefore, the nano-system realizes the organic combination of chemotherapy, gene therapy and photodynamic therapy. The results of in vitro and in vivo experiments showed that the anti-tumor effect of the triple combination therapy was significantly better than that of the single therapy. Ho et al. Used β-CD to complex superhydrophobic fluorocarbons modified on the surface of mesoporous silicon to encapsulate DOX in the pores, thus obtaining a chemotherapy-sonodynamic combination therapy nanosystem[109]. After the nano-system is gathered at the tumor focus, the beta-CD falls off to expose the surface of the super-hydrophobic mesoporous silicon under ultrasonic irradiation, and a series of reactions such as cavitation of interface nano-bubbles (INBs), generation of ROS, rapid drug release and the like are triggered. Cavitation of IBNs can destroy tumor blood vessels and promote the accumulation and penetration of nano-carriers in tumor tissues. IBNs can exist in tumors for several days, so they can be repeatedly irradiated by ultrasound to improve the effect of chemotherapy and sonodynamic therapy. The results of in vitro and in vivo experiments confirmed that the nanosystem could achieve multimodal combination therapy of anti-tumor angiogenesis, chemotherapy and sonodynamic therapy (Fig. 7). In 2020, Zhang et al. developed a smart mesoporous silicon nanoplatform based on CuS@mSiO2@MnO2 double-layer core-shell structure, in which the mSiO2 layer was prepared from bis [-3- (triethoxysilyl) propyl] disulfide (BTEPDS) and TEOS through a co-condensation method[110]. When the system entered the tumor microenvironment (weak acidity, high GSH level), the MnO2 shell dissolved into Mn2+ and the disulfide-bonded mesoporous silica framework disintegrated, releasing the encapsulated DOX molecules and CuS nanoparticles. Due to the excellent photothermal conversion efficiency of CuS, 915 nm near-infrared light triggers significant photothermal therapy. At the same time, the generated free Mn2+ and the H2O2 have a Fenton-like reaction to generate hydroxyl radicals (.OH) with high cytotoxicity, so that the anti-tumor effect of the chemodynamic therapy is fully exerted. In addition, the MnO2 shell improves the hypoxic condition of the tumor site by catalyzing H2O2 to produce oxygen, and enhances the effect of tumor chemotherapy. The results of tumor inhibition test in tumor-bearing mice model showed that the synergistic effect of chemodynamic therapy, photothermal therapy and chemotherapy in this system could achieve complete tumor eradication and no recurrence after 14 days of treatment. In order to enhance the radiotherapy efficacy of hypoxic tumors, Wang et al. Prepared Janus-type golden triangle plate-mesoporous silica composite nanocarriers for the delivery of hypoxic activation prodrug tirapazamine (TPZ)[111]. Because the gold nano-triangular sheet has excellent photothermal performance and radiotherapy sensitization characteristics, the Janus particles can realize the synergistic anti-tumor effect of radiotherapy sensitization and photothermal therapy. In addition, TPZ-loaded nanoparticles showed pH-responsive drug release behavior, which was helpful to enhance the therapeutic effect on hypoxic liver cancer cells. The results of animal experiments show that the nano-system organically combines hypoxia-activated chemotherapy and photothermal therapy with X-ray triggered radiotherapy, significantly inhibits tumor growth and does not cause systemic toxicity.
The use of medical imaging technology, pathological analysis and other means to achieve early detection and diagnosis of tumors, to obtain detailed pathological information such as the location, size and dissemination of tumor lesions, is the basis and prerequisite for precise treatment of cancer. Only by accurately detecting the condition of the lesion in the early stage can we formulate and implement an effective cancer treatment plan. It is necessary to monitor the lesion site after treatment in order to evaluate the effectiveness of treatment. However, a single treatment lacking accurate diagnostic information can not achieve the desired anti-cancer effect. To this end, researchers put forward the concept of integration of diagnosis and treatment of cancer, which combines the advantages of chemistry, biology, medicine, pharmacy and nanotechnology to create a new field of nano-diagnosis and treatment. Because mesoporous silicon has the characteristics of high porosity, diversified structure and easy surface modification, a multifunctional mesoporous silicon nano diagnosis and treatment platform can be designed and constructed, which integrates the functions of tumor diagnosis, treatment and monitoring. In recent years, some researchers have combined mesoporous silicon intelligent delivery system with imaging materials to endow the delivery system with dual functions of diagnosis and treatment. This kind of nano-diagnosis and treatment system can accurately locate and diagnose tumor lesions with the help of clinical imaging technology (such as magnetic resonance imaging (MRI), computed tomography (CT), photoacoustic imaging (PAI), etc.).In addition, the carried drug can be released on demand in a fixed-point and quantitative manner to efficiently kill cancer cells, and the transport process and therapeutic effect of the nano-drug can be tracked in real time through imaging technology, thereby providing important guiding information for further adjustment of the treatment plan. For example, Dai et al. designed a pH-responsive mesoporous silica nanocarrier for targeted drug delivery and optical imaging[112]. They first synthesized dendritic mesoporous silica nanoparticles (HPSN) with hierarchical pore structure by ether microemulsion method, and then modified the surface of HPSN with carboxyl groups.N-phenylenebis (salicylideneimine) dicarboxylic acid (Salphdc) and In3+ form coordination macromolecules through coordination with carboxyl groups, and these macromolecules, which are unstable under acidic conditions, are deposited on the surface of mesoporous silica to block the mesoporous channels, and are further coupled with the targeting ligand folic acid on the surface. In this nanosystem, Salphdc not only acts as a stimuli-responsive gating motif, but also serves as an excellent fluorescent probe for tracking the endocytosis process and in vivo biodistribution of nanocarriers. The results of in vitro and in vivo experiments show that the nano-diagnosis and treatment system can efficiently deliver DOX to tumor sites, and significantly induce apoptosis and inhibit tumor growth. In addition, Rao et al. constructed a novel mesoporous silicon-based smart nano-diagnostic agent for magnetic resonance imaging-guided chemotherapy and photodynamic synergistic anti-tumor therapy by connecting the contrast agent Gd-DOTA and Ce6-PEG conjugate as ROS-responsive gating and ROS-generating agents to the surface of amino-functionalized mesoporous silicon through amidation reaction[113]. Since the Gd-DOTA chelate is sensitive to ROS, the nanosystem is able to control the DOX on-demand release process with photodynamic therapeutically generated ROS and shows enhanced T1-MR imaging signals. In vivo biodistribution studies found that NIR fluorescence imaging and T1-weighted magnetic resonance imaging both showed that a large number of nanocarriers accumulated in the tumor site 6 hours after intravenous injection, so they carried out 660 nm laser irradiation 6 hours after injection, triggering photodynamic therapy and chemotherapy successively. The results of the in vivo trial showed that the nanosystem was able to significantly inhibit tumor growth through this imaging-guided chemotherapy in combination with photodynamic therapy, in sharp contrast to single-mode therapy (chemotherapy or photodynamic therapy).

4.2 Antimicrobial application of mesoporous silica-based smart delivery system

Since the advent of antibiotics in the mid-20th century, the mortality rate of bacterial infectious diseases has been greatly reduced. However, with the large-scale abuse of antibiotics in recent years, bacteria have gradually become resistant to traditional antibiotics, that is, the so-called "super bacteria". A study carried out by the European Food Safety Authority (EFSA) and the European Centre for Disease Prevention and Control (ECDC) in 2016 showed that common Salmonella, Campylobacter, Escherichia coli and Staphylococcus aureus had increased resistance to certain antibiotics[114]. In addition, bacteria have an innate self-defense mechanism, namely biofilm, which refers to the three-dimensional structural community formed by bacteria embedded in the extracellular polymeric matrix secreted by themselves. The morphology and physiological functions of bacteria in biofilm are significantly different from those of free strains, and the tolerance to antibiotics can be increased by 10 to 1000 times[115]. The combination of these two adverse factors significantly increases the resistance of bacteria to antibiotics, weakens the effect of conventional antimicrobial therapy, and causes stubborn infectious diseases. In view of the increasingly serious problem of bacterial resistance, it is urgent to develop an efficient antibiotic delivery system to replace the traditional antimicrobial therapy for the treatment of drug-resistant bacterial infectious diseases. In recent years, MSNs have been widely used to construct drug controlled release systems due to their unique structural characteristics and physicochemical properties. Mesoporous silicon itself has no antibacterial effect, but the use of mesoporous silicon to carry antibiotics can improve their pharmacokinetic and pharmacodynamic characteristics, and enhance their durability and effectiveness[116⇓~118]. In addition, the interaction between MSNs and bacteria and the permeability of MSNs to biofilms can be enhanced by adjusting the particle size and surface functionalization, and MSNs can interfere with the communication between bacteria (i.e., quorum sensing) to hinder the formation of biofilms[119,120]. In conclusion, the mesoporous silica-based drug delivery system provides a new strategy to solve the global problem of bacterial resistance.
Compared with normal tissues, the sites of bacterial infection have significantly different microenvironments, which are characterized by local pH decline and overexpression of specific enzymes. There are two reasons why the microenvironment is acidic: (1) the proliferation of bacteria consumes oxygen, triggering anaerobic metabolism of bacteria, and bacteria secrete organic acids (including lactic acid and acetic acid); (2) the host immune response triggers an inflammatory response, upregulating the expression of a variety of inflammatory factors, including cytokines and C-reactive protein, which make the site of infection more acidic[121]. Similar to tumor cells, bacteria can secrete a variety of enzymes in the stroma, including lipase and hyaluronidase, which promote the formation and stability of biofilm[122]. Therefore, using these specific physiological stimuli, researchers can construct an "active defense" intelligent drug controlled release system for the efficient treatment of bacteria-induced infectious diseases. For example, Chen et al. constructed a pH-responsive calcium phosphate-coated mesoporous silica antibacterial system by electrostatic attraction and biomineralization[123]. Due to the acid instability of calcium phosphate, the nanocarrier showed a pH-sensitive drug release behavior, and the cumulative release amount in 48 H at pH = 4. 5 was up to 92%. The introduction of the targeted ligand folic acid (FA) effectively enhanced the uptake efficiency of the material by cells, significantly weakening the drug efflux effect of E. coli and S. aureus. The results of in vitro antibacterial experiments confirmed that ampicillin (Amp) loaded nano-carriers can effectively overcome the multi-drug resistance of bacteria, improve the bioavailability of drugs, and reduce the content and activity of bacterial proteins, thus inducing the rupture of bacterial membranes and the death of bacteria. In addition, the results of in vivo experiments showed that the nanocarrier could efficiently deliver Amp to the site of bacterial infection, effectively kill multidrug-resistant strains and promote rapid wound healing (fig. 8). Sun et al. constructed a hyaluronidase (Hyal) -responsive mesoporous silica-based delivery system for chemotherapy-photothermal synergistic treatment of drug-resistant strains[124]. They first embedded gold nanorods in mesoporous silicon and modified the surface with amino groups, and then coated hyaluronic acid (HA) on the surface of mesoporous silicon through amidation reaction. When the nanosystem reaches the site of infection, Hyal secreted by bacteria specifically degrades the HA coating, triggering the release of cinnamaldehyde (CA) in the pore. This on-demand release mechanism significantly improves the bioavailability and therapeutic selectivity of the drug. Due to the superior photothermal conversion ability of gold nanorods, the system produces a strong photothermal effect under the irradiation of 808 nm near-infrared light. In vitro experiments showed that the nanocarrier could achieve chemotherapy-photothermal synergistic antibacterial effect, reduce the dosage and enhance the antibacterial efficacy (MRSA inhibition rate was up to 90%). In-depth and comprehensive in vivo tests were conducted using a mouse model of MRSA infected wounds, and the results showed that the synergistic antibacterial system showed strong bactericidal effect and wound healing ability, which provided a potential therapeutic strategy for curing drug-resistant bacterial infections.
In addition to endogenous stimulus-responsive controlled-release systems, researchers have also developed exogenous stimulus-responsive "passive defense" intelligent drug delivery systems. Compared with internal physiological stimuli, the characteristic parameters of external physical stimuli (such as frequency, intensity, irradiation site, application time, etc.) Can be adjusted freely according to needs, so this kind of delivery system can achieve precise release of antibacterial drugs at specific infection sites and significantly improve the antibacterial effect of drugs. For example, Yu et al. reported a magnetic supramolecular-gated mesoporous silica-based nanocomposite simultaneously loaded with the antimicrobial peptide melittin (MEL) and the antibiotic ofloxacin (OFL)[125]. The system was assembled from macroporous mesoporous silica modified by β-CD-PEI conjugate (H, MSNLP @ PEICD) and adamantane-terminated magnetic mesoporous silica (G, MagNP @ MSNA-CB [6]) with cucurbituril [6] through host-guest inclusion. Under the stimulation of pathogens and alternating magnetic field (AMF), the supramolecular valve can release high molecular weight MEL and low molecular weight OFL simultaneously. Compared with free MEL and OFL, the combined delivery system (H-MEL + G-OFL) showed higher biofilm eradication capacity, completely removed biofilm biomass and killed pathogenic bacteria, while having no significant toxicity to mammalian cells. In addition, an in vivo implant model test shows that the nanocarrier can efficiently remove the pathogenic bacteria biofilm in the implant through the combined delivery of the MEL and the OFL, and avoid the host tissue from being damaged or generating an inflammatory reaction.

4.3 Application of mesoporous silica-based smart delivery system in the treatment of diabetes

Diabetes mellitus is a metabolic disease characterized by chronic hyperglycemia, which has become the third fatal disease after cardiovascular and malignant tumors. According to the different pathogenesis, diabetes is mainly divided into two types: type I diabetes and type II diabetes. Type I diabetes is mainly characterized by insufficient insulin secretion caused by autoimmune injury of islet beta cells, while type II diabetes is mainly characterized by insulin resistance, that is, the physiological effect of insulin on related tissues is weakened[126,127]. At present, the main treatment of type I diabetes is to supplement exogenous insulin by injection, while type II diabetes also requires appropriate insulin intake to maintain the stability of blood sugar levels. However, long-term insulin injection is prone to the risk of excessive insulin use, which leads to a series of side effects, such as hypoglycemia, hyperinsulinemia and lipoatrophy[128]. The rise and development of intelligent drug delivery systems, which can release insulin on demand, reduce side effects, and improve patient comfort and quality of life, has brought hope to solve the drawbacks of long-term injection delivery.
Based on the pathological characteristics of high blood glucose levels, researchers have designed glucose-responsive mesoporous silicon-based intelligent delivery systems, which can simulate the behavior of pancreatic beta cells to "secrete" insulin, that is, to spontaneously regulate the release rate and amount of insulin according to real-time blood glucose levels, so as to avoid side effects caused by overdose. Glucose-responsive modules are the key building blocks for such delivery systems. Commonly used glucose-responsive modules include glucose oxidase (GOx) and phenylboronic acid (PBA). GOx can specifically catalyze the oxidation of glucose in the microenvironment to produce gluconic acid and H2O2, resulting in local acidity, hypoxia and increased concentration of H2O2 in the microenvironment. Using these property changes, a glucose-responsive intelligent delivery system based on GOx can be developed. For example, Xu et al. developed a blood glucose responsive microneedle transdermal drug delivery system by combining soluble microneedles with smart mesoporous silicon nanocarriers[129]. They first modified the H2O2 sensitive 4- (imidazolylcarbamate) phenylboronic acid pinacol ester (ICBE) on the surface of amino-functionalized mesoporous silicon, and then encapsulated insulin and GOx in the mesoporous channels by the host-guest interaction between α-CD and phenylboronic acid ester. Then, the prepared H2O2 sensitive mesoporous silica drug delivery system was mixed with water-soluble polymer polyvinylpyrrolidone (PVP) by template method, and finally the microneedle transdermal drug delivery system was prepared. After penetrating the skin tissue, GOx converts blood glucose into gluconic acid and produces H2O2, which is oxidized and decomposed, triggering the release of insulin. Using diabetic rats (Spranue Dawley, SD rats) as a model, the results of the microneedle patch transdermal drug delivery test showed that the microneedle patch transdermal drug delivery system could significantly reduce the blood glucose level, and the duration of drug efficacy was longer than that of direct insulin injection. Therefore, the combination of insulin-loaded mesoporous silica smart nanocarriers and microneedles has great potential for transdermal drug delivery.
Different from the action mechanism of GOx, phenylboronic acid can reversibly covalently bind to the cis-dihydroxy group on the carbohydrate molecule to form cyclic boronic acid esters. Taking advantage of the difference in binding constants between carbohydrate molecules and PBA, researchers can use competitive binding mechanisms to build a glucose-responsive intelligent delivery system based on PBA. For example, Hou et al. prepared a glucose-sensitive, self-regulating, intelligent insulin delivery system[130]. They first modified the surface of mesoporous silica with phenylboronic acid by amidation reaction, and then attached sodium alginate (SA) to the surface of the support through boronic acid ester bond after loading insulin. Under normal blood glucose conditions, the covalent interaction between the syn dihydroxy group of SA and phenylboronic acid remains stable, and insulin cannot leak out. In a high-glycemic environment, glucose molecules compete to bind to phenylboronic acid on the surface, triggering the opening of the nano-valve and the release of insulin. The results of in vivo study in type 1 diabetic mice showed that the system could achieve the site-specific sustained release of insulin and maintain the normal blood glucose level of mice for more than 12 hours without obvious side effects. The hypoglycemic effect of the system is significantly superior to that of conventional therapeutic agents Novolin 30R and Novolin R. In addition, in vivo experiments also showed that complications such as lipid metabolism disorders and organ damage in diabetic mice were effectively alleviated after nano-drug treatment (Fig. 9).
Compared with injection, oral insulin is considered to be the most reasonable way of administration because of its simple operation and similar delivery mechanism with endogenous insulin[131]. However, oral insulin administration has an important drawback, that is, the strong acidity of gastric juice and various digestive enzymes in the gastrointestinal tract lead to the easy degradation of insulin, which makes it lose its pharmacological effect. In order to improve the bioavailability and hypoglycemic effect of insulin during oral administration, researchers have developed pH-responsive oral drug delivery carriers to protect insulin from degradation in gastric juice and promote efficient intestinal absorption of insulin. For example, Sun et al. reported a pH and glucose dual-responsive mesoporous silica-based oral nano-drug delivery system[132]. They first coated pH-sensitive dextran-maleic acid (Dex-Ma) units on the surface of mesoporous silica by radical polymerization, and then coupled glucose-sensitive 3-aminophenylboronic acid (APBA). This dual sensitivity of pH and glucose is very beneficial to the loading and release of insulin. Under alkaline conditions (pH = 9.0), the PBA group is electronegative, which leads to the swelling of the dextran shell and contributes to the efficient loading of insulin. In the neutral environment, the uncharged PBA group causes the shell to shrink and seals the outlet of the channel. Aft that nano medicine is orally taken, the strong acid medium in the stomach further contracts the shell to prevent the insulin from release in advance in gastric juice. Once in the small intestine (pH 7-8), the PBA group is converted to a charged form by the action of blood glucose, and the shell swells to expose the mesopore orifice, allowing insulin to be released. Due to the affinity of PBA to the glycoprotein on the cell membrane, the nanocarrier can enhance the penetration of insulin in the intestinal epithelium and promote the absorption of insulin in the villi. The results of in vivo studies confirm that the oral insulin delivery platform can improve the pharmacological effects of insulin and significantly reduce blood glucose levels.

4.4 Application of mesoporous silica-based smart delivery system in the treatment of other diseases

In addition to the above diseases, researchers have also constructed new mesoporous silicon-based intelligent nanocarriers for the treatment of other types of diseases, using physiological stimuli related to disease microenvironment or drug delivery routes to trigger the controllable delivery of therapeutic drugs, enhance their therapeutic effects and reduce toxic and side effects. Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by severe decline in cognitive and memory functions. The occurrence of AD is usually associated with the accumulation and deposition of misfolded Amyloid-β (Aβ) in the brain. The aggregated Aβ protein folds into insoluble fibrils in the central system, and eventually deposits into amyloid plaques, leading to normal neuronal damage[133]. An important pathological feature of AD is the abnormal increase of metal ion concentration (such as Zn2+, Cu2+, etc.), which is considered to be one of the important factors in the pathogenesis of AD. Related studies have shown that high concentrations of metal ions can easily induce the aggregation and deposition of Aβ protein, and cause oxidative stress, that is, the increase of ROS level, resulting in nerve cell damage[134]. Therefore, the high concentration of metal ions in the brain is considered as a target for the treatment of AD. In theory, metal chelators can inhibit the aggregation of Aβ protein induced by metal ions, block the generation of ROS, and alleviate the pathological characteristics of AD patients. However, these therapeutic agents can not effectively pass through the blood-brain barrier (BBB), and their efficacy is greatly weakened. The nano drug delivery system can obviously prolong that blood circulation time of the drug, and the prolongation of the circulation time enhance the endocytosis of endothelial cells in brain capillary to the delivery system,Then the delivery system is transported to the brain tissue through the endocytic transport of efflux, that is, endocytosis and endocytic transport mechanism are the main ways for nano-drugs to penetrate the blood-brain barrier and reach the brain tissue. Therefore, the nano-drug delivery system can improve the efficiency of metal chelators through the BBB, which is of great significance for the treatment of AD[135]. For example, Liu Jie's team constructed a mesoporous silicon nanocarrier (MSN-CQ-AuNPs) encapsulated with H2O2 responsive gold nanoparticles (AuNPs) for the treatment of AD[136]. They first modified the surface of mesoporous silica with phenylboronic acid, and then functionalized AuNPs with β-D-glucose through the coupling of phenylboronic acid ester bond. In the pathological environment of AD with high concentration of H2O2, the cleavage of the phenylboronic acid ester bond induced the detachment of AuNPs from the surface of the material, and the loaded metal chelator clioquinol (CQ) was released. In addition, the nanosystem can effectively penetrate the blood-brain barrier and significantly inhibit Aβ fibrosis and aggregation induced by Cu2+. At the same time, the system can alleviate a series of toxic and side effects caused by Aβ40-Cu2+, including cell membrane rupture, vascular defects and apoptosis caused by reactive oxygen species.
Mesoporous silica-based smart delivery systems also have good application prospects in the treatment of colon diseases, such as inflammatory bowel disease. For example, Teruel et al. designed an enzyme-responsive magnetic mesoporous silica-based oral nanocarrier for colon-targeted drug delivery[137]. They coupled a bulky azo derivative on the surface of magnetic mesoporous silica (Fe3O4@MSNs) to block the mesoporous channels to prevent the leakage of hydrocortisone. In the azoreductase-rich environment of the colon, hydrocortisone is released from the orifice due to cleavage of the azo bond. The release study based on the in vitro digestion model (mouth → stomach → small intestine → colon) showed that the amount of drug released from the system was very limited before reaching the colon, but a large amount of drug was released when the system was in the colon environment. In addition, the retention time of the magnetic carrier in the colon can be prolonged by using the guidance of an external magnetic field, and the therapeutic effect can be enhanced. In vivo efficacy studies in rats with colitis infection demonstrated that the hydrocortisone-loaded magnetic mesoporous silica nanosystem significantly reduced the colon/body weight ratio and clinical activity scores. In addition, histological studies showed that the inflammation was greatly reduced after treatment, and even normal mucosal tissue was regenerated.
In addition, chronic heart failure is a serious clinical syndrome, one of the important pathological features of which is the abnormal increase of H2O2 levels in myocardial tissue. Therefore, the use of H2O2 responsive nanocarriers to deliver drugs is a feasible strategy for the treatment of this disease. For example, Tan et al. Constructed a new multifunctional mesoporous silica delivery system for the treatment of heart failure, which has the functions of simultaneous detection of H2O2 and targeted drug release[138]. They first attached fluorescent molecules (FL2) that could induce H2O2 to the surface of mesoporous silicon, and then coated α-CD on the surface of the material through host-guest interaction. Endogenous H2O2 at the lesion site removed the borate group of FL2, weakened the binding force between FL2 and α-CD, promoted the shedding of macrocyclic molecules and triggered the release of captopril, while turning on the fluorescence function of FL2. The in vitro sensing study showed that the fluorescence intensity of the nanosystem was linearly related to the concentration of H2O2, which confirmed the H2O2 sensing function of the nanosystem. They evaluated the anti-heart failure efficacy of the nanosystem using a KillerRed-induced zebrafish chronic heart failure model, and the results showed that the system could significantly improve the heart rate and cardiac output of zebrafish with heart failure, and its therapeutic effect was significantly better than that of free captopril (Fig. 10).

5 Conclusion and prospect

Mesoporous silica has attracted great attention in the biomedical field, especially in the field of drug delivery, due to its advantages such as adjustable morphological parameters (including shape, particle size, pore size and pore volume), large specific surface area, various surface functionalization and good biocompatibility. The smart delivery system based on mesoporous silica realizes the precise and controllable release of loaded drugs in time and space dimensions by triggering the structural transformation of surface gating switches with external stimuli (including endogenous physiological signals and exogenous physical stimuli), which is of great significance for the safe and efficient treatment of diseases. In recent years, the design and development of new mesoporous silicon-based smart delivery systems have become the focus of research, and rich and diversified creation schemes have emerged, showing good application prospects in the treatment of various diseases. In this paper, the construction strategies of mesoporous silica-based smart nanocarriers in recent years are summarized, including drug loading strategy and gated release strategy. In this paper, we focus on the establishment of various types of gating switches and reveal their mechanisms of action, which endow the nanocarriers with stimuli-responsive properties, and the gating switches are driven by specific stimuli (such as pH, redox, enzyme, light, etc.) From the initial off-state to the on-state, so that the guest molecules are released in a controllable manner. Subsequently, the application status of these smart nanocarriers in the treatment of various diseases (not limited to cancer) is elaborated, the design ideas of smart nanocarriers for specific diseases and the biomedical role of representative systems are described, and the great application potential of mesoporous silicon-based smart delivery systems in the treatment of diseases is highlighted.
Although some important progress has been made in the application of mesoporous silica-based smart delivery systems in the treatment of diseases, there are still some key issues to be solved to meet the needs of practical clinical applications: (1) The biological safety of mesoporous silica-based nanocarriers. Although numerous in vitro and in vivo studies have confirmed that mesoporous silica is basically non-toxic and immunogenic, some studies have put forward the opposite view that mesoporous silica may cause side effects such as hemolysis, inflammation, neurotoxicity, hepatotoxicity and so on[139,140]. The toxicity effect of mesoporous silica is influenced by the shape, size, surface charge and functional groups of mesoporous silica. These facts indicate that the biosafety evaluation of mesoporous silica needs to be further explored, and the long-term toxic effects (including immune system toxicity, cardiac toxicity, liver toxicity, kidney toxicity and lung toxicity), biodegradation behavior and elimination pathway in vivo of mesoporous silica system need to be comprehensively and systematically studied. (2) Scalability and reproducibility of the production process of mesoporous silica-based nanocarriers. The large-scale production of mesoporous silica-based nanocarriers is an important prerequisite for their clinical application, which requires the production process of drug carriers to leap from low-yield laboratory scale to ultra-high-yield industrial scale. It is a major challenge to maintain the consistency of morphology and properties of nanocarriers in this transformation process, and the significant increase in manufacturing costs will also hinder the industrialization of mesoporous silica-based nanocarriers. In order to overcome these limitations, researchers need to take various effective measures, including simplifying and standardizing the production process and developing low-cost silicon sources and coupling agents. (3) The structural complexity of mesoporous silica-based nanocarriers. In order to meet the needs of therapeutic applications in complex pathological microenvironments, the design of mesoporous silica-based nanocarriers reported in recent years tends to be multi-functional and integrated in diagnosis and treatment, involving various types of functional modules. These carriers often have the problem of "over-design", and their structures are more complex. It is well known that the larger the number of components contained in a drug carrier, the greater the risk of uncertainty in treatment and the smaller the likelihood of clinical approval. Therefore, when designing mesoporous silica nanocarriers, we need to pay attention to the balance between structural complexity and functional diversity, simplify the system design as much as possible, eliminate redundant components and ensure the integrity of the required functions, that is, to establish a concise and effective drug delivery system. (4) The consistency of in vitro and in vivo experimental results of mesoporous silica-based nanocarriers. A large number of literatures have confirmed the on-demand release ability and targeted delivery of mesoporous silicon-based intelligent carriers under specific stimuli in vitro. However, the existence of multiple physiological barriers (including blood barrier, tissue barrier and cell barrier) and complex pathological environment in organisms will hinder the specific accumulation and controlled release of nano-carriers in target tissues, which will easily lead to negative results in vivo experiments. Therefore, researchers need to adopt biocompatible polymer coating (such as polyethylene glycol), biomimetic camouflage (such as cell membrane embedding), targeted ligand modification (such as RGD peptide) and other strategies.A mesoporous silicon-based nano-delivery system with "stealth" function (that is, it can escape the clearance of the immune system in vivo) and the ability of target tissue enrichment and penetration (that is, it can achieve specific accumulation and efficient penetration and diffusion in pathological tissues) has been developed. In addition, because the number of mesoporous silica-based systems in the clinical trial stage is very limited and these tests have not yet reached a clear conclusion,At present, it is impossible to determine whether the distribution, accumulation, degradation and metabolism of mesoporous silica in human body are similar to those in model animals, which requires the continuous attention and exploration of researchers[141⇓⇓⇓~145]. It is believed that with the continuous innovation of nanotechnology and the further deepening of follow-up research, mesoporous silicon-based intelligent delivery system will eventually overcome various difficulties and enter clinical practice, realize the organic unity of disease diagnosis and treatment, and promote the vigorous development of personalized precision medicine, so as to protect human health.

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Funding

National Natural Science Foundation of China(52072177)

Fundamental Research Funds for the Central Universities(30918012201)

Fundamental Research Funds for the Central Universities(30919011405)

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