Application Summary of Mesoporous Silica Nanoparticles (MSN) in Controlled Drug Release

Porousness silica antiparticles (MSN) have become the core carrier material of controlled drug delivery systems due to their advantages such as adjustable pore size, large specific surface area, and good bio compatibility. This article reviews the characteristics, drug loading mechanism, drug controlled release mechanism, targeting function, and future prospects of MSN, with specific contents as follows:

1. Basic Characteristics and Advantages of MSN

1.1 Structure and Synthesis

In 1992, Kresge et al. first reported MCM-41 type mesoporous molecular sieves in Nature, and MSN has been gradually developed since then. Its synthesis uses organic molecules (surfactants or amphiphilic block polymers) as templates, reacts with inorganic silicon sources to form ordered assemblies, and after removing the templates by calcination or solvent extraction, a porous silica framework is obtained. By selecting different templates and synthesis methods, MSN with different structural characteristics (e.g., pore size, pore morphology) can be prepared.

1.2 Core Advantages

•Physicochemical Properties: The mesoporous pore size can be continuously adjusted within 2-50 nm, with a specific surface area of >900 m²/g and a specific pore volume of >0.9 cm³/g. The framework is stable, and the inner and outer surfaces are easy to modify, enabling it to load a variety of drugs and achieve sustained release, extending the drug effect.

•Biocompatibility: Studies by the Lin research group have shown that when the concentration of MSN is below 100 μg/mL per 10⁵ cells, it has no impact on cell survival and proliferation; after cell absorption, the cell membrane remains intact and mitochondrial activity is normal. Animal experiments have shown that silica gel has no toxicity within 42 days of implantation and can be safely used as a drug carrier.

•Intracellular Endocytosis Capacity: The particle size of MSN can be adjusted within 50-300 nm, which is suitable for endocytosis of non-phagocytic eukaryotic cells (the absorption efficiency is the highest at a particle size of approximately 200 nm). It can be rapidly endocytosed by cancer cells (HeLa, CHO, etc.) and non-cancer cells (astrocytes, hepatocytes, etc.), and can be observed in cells within 30 minutes. It has strong affinity with phospholipids and can enter cells through clathrin-mediated pathways. Modification of some functional groups (e.g., folic acid, charged groups) can also improve endocytosis efficiency and help escape from endolysosomes.

2. Drug Loading Mechanism of MSN Drug Delivery Systems

2.1 Core Influencing Factors of Drug Loading

•Pore Size Matching: The pore size of MSN must be slightly larger than the size of drug molecules (pore size/drug size > 1) to achieve effective drug adsorption.

•Interactions: Hydrogen bonds, ionic bonds, electrostatic, and hydrophobic interactions between the mesoporous surface and drugs are the main driving forces for drug adsorption. At the same time, weak interactions between drug molecules can fill the mesopores, further improving the drug loading rate.

•Specific Surface Area and Specific Pore Volume: Within the allowable range of pore size, the larger the specific surface area, the more drugs can be adsorbed (e.g., MCM-41 has a specific surface area of 1157 m²/g, with a maximum alendronic acid loading capacity of 139 mg/g; SBA-15 has a specific surface area of 719 m²/g, with a maximum loading capacity of 83 mg/g). The larger the specific pore volume, the higher the drug loading potential. Multiple loadings can maximize the filling of mesopores through interactions between drug molecules, improving the drug loading capacity.

2.2 Comparison with Other Drug Delivery Systems

Type of Drug Delivery System	Core Characteristics	Suitable Scenarios
Microemulsion	Improves drug solubility and stability; has sustained release and targeting properties; easy for industrialization	Transdermal absorption preparations
Biodegradable polymer nanoparticles	Changes the in vivo distribution of drugs; suitable for oral administration of peptide and protein drugs	Oral formulations of genetic engineering drugs
Liposomes	High modifiability; can prepare stealth/immunoliposomes; reduces drug toxicity	Drug delivery requiring reduced toxic and side effects
Solid lipid nanoparticles	Uses low-toxic lipid materials; can be industrialized by high-pressure homogenization; high drug loading capacity	Preparations requiring high drug loading and easy industrialization
Magnetic nanoparticles	Targeting to the lesion site via external magnetic field	Treatment of superficial lesions or lesions easily accessible by magnetic fields
MSN	Adjustable pore size, large specific surface area, easy modification; has both sustained release and targeting potential	Core carrier of controlled drug release systems

3. Controlled Release Mechanism of MSN Drug Delivery Systems

Drug release is divided into uncontrolled release (uncontrollable release location and rate) and controlled release (targeted release control). The controlled release of MSN is mainly achieved through the following two types of mechanisms:

3.1 Controlled Release Based on Structural Parameters

Drug release is controlled by adjusting the pore size, pore morphology, and surface properties of MSN:

•Pore Size and Pore Morphology: The larger the pore size, the faster the drug release rate (e.g., MCM-41 loaded with ibuprofen has a shorter release cycle for samples with larger pore sizes). The connectivity and geometric morphology of pores affect release efficiency; MSN with spherical and hexagonal pores releases drugs faster than those with tubular and worm-like pores (e.g., the antibacterial activity of RTIL-MSN against E. coli K12 is better for samples with hexagonal pores).

•Surface Functionalization Modification: The silanol groups on the MSN surface can be modified with functional groups such as amino and carboxyl groups through silane coupling agents to change the interaction with drugs and adjust release:

◦Amino modification (APS post-modification method or one-step method) can improve the drug loading rate and extend the release cycle. The one-step method is more suitable for water-soluble drugs (e.g., BSA, aspirin), while the APS post-modification method is more suitable for water-insoluble drugs (e.g., ibuprofen).

◦Carboxylated MSN loads famotidine, achieving effective loading through charge interactions; the more carboxyl groups modified, the higher the drug loading capacity.

◦Collagen-modified SBA-15 can inhibit the release of drugs (e.g., atenolol) and enhance the sustained release effect.

3.2 Controlled Release Based on Stimuli-Responsiveness ("Gatekeeper" System)

In 2003, Lin et al. proposed the "gatekeeper" mechanism, which uses chemical entities (nanoparticles, organic molecules, etc.) to block MSN pores. The "gatekeeper" is opened under external stimulation to release drugs, achieving "zero release" (no release before reaching the lesion site) and reducing toxic and side effects. The main response types include:

•pH Responsiveness: Introduce pH-sensitive switches (e.g., carbon chains containing amino groups) at the outer outlet of MCM-41. Under low pH (e.g., tumor microenvironment), amino groups are protonated, and electrostatic repulsion closes the "valve"; under high pH, amino groups are deprotonated, and carbon chains aggregate to open the "valve," controlling drug release.

•Light Responsiveness: Use gold nanoparticles modified with photosensitive elements (e.g., TUNA) (PR-AuNPs) to block MSN pores. Specific excitation light (e.g., 365 nm) triggers the reaction of photosensitive elements, opening the pores to release drugs.

•Temperature Responsiveness: When the temperature is lower than the lower critical solution temperature (LCST), drugs (e.g., ibuprofen) form hydrogen bonds with MSN and are trapped; when the temperature is higher than the LCST (e.g., tumor tissue temperature), hydrogen bonds break to release drugs, suitable for targeted release of anti-tumor drugs.

•Enzyme Responsiveness: For example, porcine liver esterase catalyzes the hydrolysis of the "plug" (ester structure) in MSN pores, causing β-CD to detach and release the drugs in the pores.

•Competitive Binding Responsiveness: MSN is connected to DB24C8 supramolecules. Metal cations competitively bind with supramolecules, breaking their connection with MSN, and the "gatekeeper" falls off to release drugs.

4. Targeting Function of MSN Drug Delivery Systems

The targeting function can increase the drug concentration at the lesion site and reduce toxic and side effects on normal cells. MSN achieves targeting mainly through the following three methods:

4.1 Ligand Targeting

Using receptors overexpressed on the surface of tumor cells (e.g., folate receptors), ligands (e.g., folic acid) are modified on the MSN surface to achieve targeting through receptor-mediated endocytosis:

•Example: Rosenholm et al. modified MSN with PEI, then connected the fluorescent molecule FITC and folic acid ligand. The endocytosis amount of cancer cells with high folate receptor expression was more than 5 times that of normal cells, achieving both targeting and labeling functions.

•Advantages: Suitable for various tumors with high folate receptor expression, such as ovarian cancer, breast cancer, and lung cancer, with strong specificity.

4.2 Magnetic Targeting

Combine magnetic particles with MSN (in two forms: magnetic particles as the core and MSN as the shell; magnetic particles adsorbed on the MSN surface), and guide them to the lesion site through an external magnetic field:

•Examples: Wu et al. prepared composite particles with Fe₃O₄ as the core and MSN as the shell; Giri et al. used superparamagnetic iron oxide nanoparticles to seal MSN pores, where iron oxide not only achieves targeting but also acts as a "gatekeeper" to control release; Liong et al. modified phosphate groups, folic acid, and fluorescent molecules on the surface of the core-shell structure, achieving both targeting and imaging functions.

•Advantages: Suitable for superficial lesions or lesions easily accessible by magnetic fields; targeting efficiency can be adjusted by magnetic field strength.

4.3 Quantum Dot-Assisted Targeting

Quantum dots (semiconductor nanocrystals with a core-shell structure) have both fluorescent labeling and targeting potential:

•Characteristics: They do not damage the activity of biomacromolecules, have a single coupling method, and can be used as a "ruler" to estimate the MSN pore size (if the quantum dot size matches, it can enter the mesopores, which can be verified by the fluorescence emission spectrum).

•Application: Modify quantum dots on the surface of magnetic MSN, combining magnetic targeting and fluorescence imaging to achieve "targeting-imaging" integration, assisting drug delivery and efficacy monitoring.

5. Summary and Outlook

5.1 Research Achievements

MSN has made significant progress in controlled drug delivery systems: it can achieve precise drug controlled release through structural adjustment and stimuli responsiveness, achieve targeting by combining ligand, magnetic, quantum dot, and other technologies, and gradually develop towards multi-functional composite systems of "imaging-targeting-multi-responsive controlled release" (e.g., quantum dot labeling + magnetic targeting + pH responsiveness).

5.2 Unsolved Problems

•Insufficient In Vivo Research: Issues such as the circulation of MSN in the blood, potential immune responses, and tissue accumulation (e.g., in the liver) have not been clarified.

•Long-Term Biocompatibility: Current studies are mostly short-term experiments; long-term degradation and toxicity need further verification.

•Expansion of Controlled Release Mechanisms: Existing response types still need to be enriched to adapt to more disease microenvironments.

5.3 Future Directions

In the future, through the development of new synthesis methods and optimization of "multi-functional integration" design (e.g., adding enzyme responsiveness, glucose responsiveness, etc.), existing bottlenecks will be solved, promoting the transformation of MSN drug delivery systems from the laboratory to clinical applications and providing more efficient and safe solutions for disease treatment.

Source: The original article synthesizes multiple research literatures, systematically reviews the application of MSN in controlled drug release, covering core links such as drug loading, controlled release, targeting, and cutting-edge directions.