Polysaccharide-Coated Mesoporous Silica Nanoparticles: Engineering Smarter Oral Drug Delivery Systems Through Surface Functionalization and Stimuli-Responsive Release

Oral drug delivery is the most prescribed and preferred systemically delivered drug delivery form and the attrition rate of orally delivered drug candidates is still a challenge for pharmaceutical scientists in their drug discovery and development process to clinical stage [1]. The estimates are consistently that around 40% of all approved drugs and as high as 90% of new molecular entities in development are in BCS Classes II and IV respectively, which are the classes characterized as having low aqueous solubility with good permeability and the combination of poor aqueous solubility and poor membrane permeability [2]. The implication of this distribution in practice is that, for most modern drug candidates, dissolution in gastrointestinal fluid rather than the passage of the drug across the epithelium is the key rate-limiting step in the attainment of systemic exposure [3]. All conventional pharmaceutical approaches to solving this problem have given incremental improvements in dissolution rate, but each with its own limitation on drug loading capacity, physical stability during storage, manufacturing scalability, or lack of ability to provide controlled, site-specific release other than through promoting solubility [4].

In this context, the use of nanoparticles as drug delivery vehicles has gained significant and sustained scientific attention as a single delivery system that can overcome multiple solubility, permeation and controlled release limitations [5]. Mesoporous silica nanoparticles (MSNs) have proven to be a structurally unique and highly promising platform to deliver poorly soluble drugs orally due to their distinct functionality. The internal pore structure of these is generally ordered, and surface areas are routinely in the range of 700-1200 m²/g, allowing a drug to be loaded at concentrations that are significantly higher than those seen with soft organic carriers [6]. The ability of MSN mesopores to keep crystalline drugs in a molecularly dispersed amorphous state, which is induced by the spatial confinement resulting from the size (2–20 nm) of the channels, is critical for BCS Class II drugs, where the supersaturation at the absorption site directly determines the bioavailability [7]. One of the most cited proofs of concept for the oral MSN platform is a clinical study with 12 human subjects (IVC-01) that showed an ordered formulation of fenofibrate resulted in 54% greater oral bioavailability compared to the commercially available fenofibrate (Lipanthyl®) [8].

However, the gastrointestinal tract is a highly complex organ with structural features not fully leveraged by unmodified MSNs. Bare surfaces of silica carry a high density of negatively charged silanol groups that do not interact well with the mucus layer, lack an intrinsic mechanism of stimuli-dependent drug release and do not provide any mucoadhesion or targeted epithelial transport. The polysaccharide surface functionalization overcomes these shortcomings by introducing mucoadhesive properties, pH-sensitive swelling properties, and programmable drug-gating capabilities, which are absent in bare MSNs and are introduced by the application of biopolymers like chitosan, alginate, hyaluronic acid and pectin [9].

This review focuses on the structural rationale, functionalization chemistry, gastrointestinal barrier navigating mechanisms, stimuli-responsive release characteristics, in vivo pharmacokinetic implications, dosage form integration, and translational constraints of polysaccharide coated MSN systems as integrated oral drug delivery systems. The review is based on the large volume of literature published from 2018 to 2025 and will offer a critically evaluated, and mechanistically informed, view of the current position and potential avenues in which the platform may develop.

2.         MESOPOROUS SILICA NANOPARTICLES: STRUCTURAL ARCHITECTURE AND PHYSICOCHEMICAL ADVANTAGES AS AN ORAL DRUG CARRIER

Perhaps the most underutilized pharmaceutical property of the MSN family is its crystallographic diversity. MCM-41 was first reported by the researchers at Mobil Corporation in 1992, and has a uniform pore diameter of 2–3 nm and a p6m two dimensional hexagonal arrangement of pores, thus having one of the highest surface area materials investigated in pharmaceutical sciences. Synthesized by the triblock copolymer Pluronic P123 as the structure-directing agent, SBA-15 has a remarkably similar two-dimensional hexagonal structure, but significantly larger pore diameters (6–8 nm) and pore volumes (1.0 cm³/g) parameters that directly relate to drug load capacity and, in comparative studies, the drug-to-silica loading ratio of up to 1:1 by weight for ibuprofen [10]. MCM-48 with its 3D bicontinuous cubic structure, provides interconnected pore channels that allow for better drug diffusion; hollow MSN (HMSN) are characterized by an ordered mesopore wall and a large central cavity, which can

significantly increase the total amount of drug encapsulated in the central space, especially designed for macromolecular drugs [11]. These MSNs have short diffusion path length, which is evident in their shorter dissolution time for the drugs in vitro, when compared to the conventional hexagonal MSNs with radially-arranged smaller-pore channels emanating from the particle surface. The reason for this is that the architecture of the MSN is not prescribed, but can be chosen with deliberate consideration of the pore geometry to match the physicochemical properties of the drug to be loaded, as summarized comparatively in Table 1

[12].

A very high density of silanol groups (Si–OH) is the common chemical feature of all MSN variants that creates the electrostatic, hydrogen-bonding and covalent modification handles, on which all subsequent functionalization is built, of the inner surface of their pores. The surface of silica can have three types of silanol groups: isolated, vicinal and geminal, each with a different reactivity towards the organosilane coupling agents applied in surface modification. The versatility of these MSN surfaces is the basic underlying reason that they can be hydrophilized, made negatively charged or amine-functionalized and/or polysaccharide-decorated with a relatively minor change in process conditions and without compromising the integrity of the pores [13].

It is important to point out that the drug amorphization behavior of MSNs in the nanopores is of special interest from pharmaceutical point of view. If the pore size is less than 10 nm, such as in the case of MSN, the MCM-41, the spatial confinement will hinder the nucleation processes and cannot allow the formation of a crystal lattice, obtaining a molecularly dispersed or amorphous state of the drug. The change from crystalline diffraction peaks and melting endotherms to amorphous features has been verified by both powder X-ray diffraction and differential scanning calorimetry in studies of ibuprofen, fenofibrate and carbamazepine loaded into MCM-41 and SBA-15 and stored under appropriate conditions for more than three months. Consequential to this amorphization is its bioavailability: an amorphous drug has a higher free energy state than the crystalline form, and thus an apparent higher level of solubility and dissolution rate in GI fluid. When the dissolution rate of ibuprofen loaded onto mesoporous carriers and that of bulk crystalline ibuprofen were compared at a pH of 5.5 (which is more representative of the proximal small intestine), the release of ibuprofen from the carriers was found to be 86–93% after 45 minutes, compared to 25% for the bulk crystalline ibuprofen [13].

Pharmaceutical applications of synthesis of MSNs are most frequently achieved by sol-gel processing using a structure-directing surfactant template, usually of either cetyltrimethylammonium bromide (CTAB) for the synthesis of MCM-41, or Pluronic P123 for the synthesis of SBA-15, which is followed by calcination or solvent extraction to remove the template and open the mesopore network. The silica source (typically tetraethyl orthosilicate, TEOS), surfactant-to-silica molar ratio, reaction pH and hydrothermal temperature all influence the downstream properties of the resultant pore diameter, particle size distribution and surface silanol density, which are all relevant to the loading of drugs and the efficiency of the polysaccharide coating and the colloidal properties of the particles in simulated gastrointestinal fluids. The synthesis parameter that is most directly relevant to the optimization of oral delivery (pore diameter control for amorphisation) as well as control of the particle size

(mucosal interaction) or surface silanol density (functionalisation yield) forms the backbone for the polysaccharide coating strategies [14].

 

 

Figure: Polysaccharide Coating Strategies for MSNs

Table 2. Stimuli-Responsive Polysaccharide-Coated MSN Systems Reported for Oral Drug Delivery Trigger Mechanisms, Drug Classes, and In Vitro Release Performance

[37].

System	MS N Typ e	Polysacch aride	Drug	BC S Cl ass	Stimulu s	pH 1.2 Relea se	pH 6.8– 7.4 Release	Key Outcome
CS-coated MCM-41	MC M-41	Chitosan	Repagli nide	II	pH	<20%	>80% (pH 6.8, 6h)	Enhanced dissolutio n vs. free drug; clinical antidiabet ic activity improve ment
FA-CS coated MSN-COOH	MC M-41	Folic acid–chitosan	Piceata nnol	IV	pH	Mini mal	88%  at pH            5.5 (2h); 30%  at pH 7.4	3-fold solubility increase; pH-selective release
HMSS–N=N–CS	Holl ow MS N	Chitosan via            azo bond	Doxoru bicin	—	Enzyme (azoredu ctase)	<10%	<15% (intestin al)	Colon enzyme-triggered release; 3× lower IC50
CS/disulfid e MSN	MS N (hyb rid)	Chitosan–disulfide	DOX + p53 gene	—	Redox (GSH)	Negli gible	Negligi ble extracel lular; rapid intracell ular	GSH- triggered intracellu lar release; gene     + drug     co- delivery
Alginate–chitosan LbL MSN	SBA -15	Alginate/c hitosan bilayers	BCS II drug	II	pH (dual layer)	<15%	Progres sive release (pH 7.4 intestin al zone)	Sequentia l            pH responsiv eness; improved sustained release

 

 

Figure 2: Stimuli-Responsive Release Mechanisms of Polysaccharide-Coated MSN

7.         INTEGRATION INTO ADVANCED ORAL DOSAGE PLATFORMS AND SCALE-UP CONSIDERATIONS

The potential for a successful PS-MSN nanosystem in colloidal suspension and its eventual development into a commercial solid oral dosage form lies in a significant gap where formulation science is not necessarily the same, and may instead be just as challenging as engineering [43]. The ability of PS-MSN nanosuspensions to form stable, flowable, compressible solid intermediates while maintaining the particle size distribution, integrity of the polysaccharide coat, and amorphization of the drug free from thermal, mechanical, and drying stresses during conventional pharmaceutical manufacture is not assured. Spray drying is the most frequently used solidification process for MSN-based nanosuspensions, andcontinues to be the method of choice for transforming PS-MSN dispersions to free-flowing powder that can be filled into capsules or directly compressed. The critical process parameters that are responsible for the success of spray drying inlet temperature, feed rate, atomization air flow and aqueous feed solid content should be optimized to ensure that the moisture is removed quickly enough to maintain the amorphous state of the drug, but not so quickly that thermal exposure denatures the polysaccharide coating or causes drug recrystallization. The formulation strategy that is most consistent for the successful spray drying of nanoparticulate formulations is to co-spray dry with a water soluble carrier matrix (usually mannitol, lactose or HPMC) in a mass ratio that is optimized to ensure sufficient interparticle separation during droplet drying to prevent irreversible nanoparticle aggregation. Both the insulin-loaded chitosan nanoparticles spray-dried with and without mannitol cryoprotectant showed that the nanoparticles remained at 376 nm after reconstitution and entrapment efficiency was 98.7%, and the results showed that the choice of cryoprotectant had a great effect on the redispersibility of the formulation after spray drying. On a gram to kilogram scale, synthesis of MSNs in continuous flow and/or microfluidic reactors, monitored in-line with DLS, has been shown on MSNs with various drug-loads and of different particle types, but standardised protocols have not yet been established across these ranges [44].

For multiparticulate systems or tablets, an alternative route of consolidation is fluid bed granulation, which is an attractive method, especially in cases where the drug product undergoes some additional processing steps before it is formulated. In this method, the PS-MSN nanosuspension is sprayed as a granulating liquid on a soluble carrier (lactose, mannitol or sucrose) and the deposited nanoparticles are integrated into the granules as the moisture is evaporated by the fluidizing air flow. The results from the ibuprofen nanosuspensions stabilized with HPMC (granulated by fluid bed) showed that HPMC gave better redispersibility than PVP/VA as a stabilizer polymer and that a higher dissolution rate of the carrier material resulted in better dispersal of nanoparticles at the granule surface, which was ascribed to differences in thickness and continuity of the nanoparticle loaded layer around individual granule particles. The results are directly relevant to the granulation of PS-MSN formulations, because of the added complexity of the polysaccharide coating; when using a granulating solution containing competing cations, the ionic strength of this solution could affect the electrostatic binding of chitosan, and pre-formulation compatibility studies may be necessary to assess this effect [45].

The use of quality by design (QbD) approaches for the formulation development of PS-MSN has been growing and critical material attributes (MSN pore diameter, polysaccharide molecular weight, degree of deacetylation, drug loading) were correlated to critical quality attributes of the final dosage form (dissolution rate at pH 6.8, particle size after redispersion, hardness and friability). The use of a design of experiments methodology for this multi-variable space allows the reduction of the experimental load and the detection of interaction effects not detected by a univariate optimisation. The manufacturing process of PS-MSN nanosuspensions to granulation and compression into tablet has several potential failure points with loss of nanoparticles' integrity (as shown in Figure 3), which requires careful formulation and process design to protect the integrity of the nanoparticles. Drug crystals have been shown to be poorly dispersible, and the polysaccharide coating of PS-MSNs is ideal for improving this dispersibility and providing advantages in dispersibility and mucosal contact in patient-centricdosage forms, including mini-tablet arrays for flexible dosing of pediatric patients and orally disintegrating tablet formats which bypass the swallowing component for geriatric populations. These applications are still at a research stage but the technological paths going from liquid crystal gels, systems which form in place and gastroretentive platforms offer a way to bring these technologies to the clinic [46].

8.         BIOCOMPATIBILITY, SAFETY PROFILE, AND REGULATORY LANDSCAPE

Regardless of the type of nanoparticulate drug delivery systems (NDDS), the depth and quality of the characterization of their safety is ultimately the driving factor that determines whether a system can transition from laboratory scale research to clinical application. There are a number of precedents that provide a safety case for MSNs. The FDA has classified silica as Generally Recognised as Safe (GRAS), and it has been approved as a pharmaceutical glidant (colloidal silicon dioxide, PhEur) and as a food additive (E551 in the European Union). MSNs undergo hydrolysis in physiological conditions with production of orthosilicic acid (Si(OH)₄) as the main degradation product, a naturally occurring biologically compatible small molecule which is absorbed and excreted through renal and hepatobiliary pathways, similar to the metabolism of dietary silica [47]. MSNs are bio-degradable and bio-cleared under most of the tested conditions and in vivo studies have confirmed that they are non-toxic at oral doses below 200mg/kg in rodent models, without any tissue accumulation. The rate and extent of MSN biodegradation, which is directly relevant to chronic safety, depends on particle size, surface chemistry and pore wall thickness. Smaller particles (<100 nm) degrade faster than larger ones and functionalization with organic groups (e.g., APTES) adds hydrolytically stable Si–C bonds, thereby increasing the degradation half-life when compared with unfunctionalized silica surfaces. The effect of the extra organic layer on degradation kinetics is dependent on the polysaccharide type and the degree of crosslinking for PS-MSNs coated with polysaccharide. As a natural biopolymer, chitosan is broken down by chitinase and lysozyme, which are normally found in the gastrointestinal tract, and its degradation rate depends on its degree of deacetylation; the higher the degree of deacetylation, the slower the degradation rate since it is less susceptible to lysozyme [48]. This has been found to be a possible reason for the long time the chitosan-MSN systems spend in contact with the intestinal epithelium, which has a pharmacological benefit, but is offset by an undesirable side effect: the system stays in contact with the intestinal epithelium surface for a long time. Well-functionalized MSNs are hemocompatible based on in vitro ISO 10993 data with negligible hemolysis (<5% at therapeutic doses) and without significant changes in the morphology of erythrocytes. In comparative studies, hybrid MSNs with polymeric or polysaccharide shell have been shown to have better hemocompatibility than bare silica. However, it is important to note that the cationic surface charge of chitosan-coated MSNs is responsible for platelet activation and pro-coagulant effects in systemic delivery applications. This risk is substantially reduced for any oral administration but is important for any application of PS-MSN that extends beyond the oral route, as in the case of transcytosis into the systemic circulation for the case of PS-MSN particles. The regulatory framework of MSN-based drug products mirrors the complexity of the classification issue of hybrid organic–inorganic nanosystems in the existing pharmaceutical regulatory framework [49]. There is no clear guidance for composite particles that contain inorganic cores of silica, and an organic coating loaded with drug molecules in either the FDA

guidance for conventional drug products or the FDA guidance documents on nanotechnology. The main difficulty comes from the lack of consensus on a protocol that connects all the measurable physicochemical parameters (BET surface area, zeta potential, yield of polysaccharide coating, free pore volume after loading) to in vivo safety and efficacy endpoints. Satisfaction of the FDA's expectation that performance is predictable from physicochemical characteristics, as stated in various guidance documents regarding nanotechnology in pharmaceutics, is not currently met at the population level for MSN systems: what works for one pore size, surface modification, and drug combination is not necessarily transferable to another system even within the same particle family. This will necessitate collaboration among regulatory agencies, standards groups and the academic research community, as a consensus, inorganic-organic hybrid nanocarrier characterization and safety testing methods must be developed [50].

9.         LIMITATIONS AND FUTURE PERSPECTIVES

While the scientific rationale of polysaccharide coated mesoporous silica nanoparticles as orally delivered drug delivery system is very strong and is still gaining momentum, an honest assessment of the field requires that attention is equally paid to the challenges that lie between promising pre-clinical results and products that are available for patients to use. There are some problems that are not hypothetical. The temperature, stirring speed and water activity of the sol-gel condensation reaction are still sensitive parameters that require careful control of the process at GMP compatible volumes and are not yet reproducible at batch scale. The polysaccharide coating step adds another reproducibility problem since the deposition efficiency of electrostatic or covalent attachment depends on the molecular weight distribution and degree of deacetylation of the chitosan batch, the ionic strength of the coating medium, and the surface amount of the silanol groups on the MSN surface, which vary between the different production lots, and/or suppliers. The in vivo pharmacokinetic data, although generally favorable in direction, are almost exclusively derived from rodent studies with single doses in fasted state which do not reflect the large inter-individual variability of pH, gastric transit time, mucus viscosity or bile salt composition commonly found in the human gastrointestinal tract. There are few in vivo long-term toxicity studies specifically for polysaccharide-coated (non-PEGylated) MSN systems, rather of bare or PEGylated MSNs [51]. The best future developments, scientifically, are those in which the most mechanistic opportunities exist. The two types of dual-stimuli responsive coatings, pH and redox sensitive coatings based on chitosan-disulfide conjugate architectures as well as pH and enzyme sensitive coatings by using hyaluronic acid as a second layer, enzyme (hyaluronidase) sensitive coatings are a rational step forward from the single-trigger systems that are currently the most predominant in the literature. These designs would give better and more selective drug release profiles in association to certain anatomical compartments in the GI tract. Machine learning and computational modeling of PS-MSN design space strong drug binding, mechanistic understanding of structure-performance relationships, and optimal pore diameter, polysaccharide molecular weight, coating layer thickness and drug loading provide a way to significantly shorten the formulation development timeline [52]. Alternatively, green synthesis routes using plant-derived polysaccharides as structure-directing agents and coating materials are gaining in popularity as an alternative to the chemical functionalized CTAB-based synthesis

as it is more sustainable. First reports indicate that a relatively good pore architecture and surface chemistry are achievable by these routes. Last, but most importantly, the oral delivery of biological macromolecules, such as insulin, glucagon-like peptide-1 analogs, monoclonal antibody fragments and siRNA, is an unmet pharmaceutical need of great clinical importance, and a platform based on PS-MSN with appropriate protective polysaccharide shells that resist enzymatic degradation but still allow the molecules to pass through the epithelial barrier is scientifically sound. As a whole, this review highlights the status of polysaccharide-coated MSNs as uniquely capable oral drug delivery platform, which spans from the atomic scale of pore confinement to the macroscopic scale of solid oral dosage form performance with the structure precisely controlled and biological response rationally engineered. The key challenge for the field is the ability to merge reproducible manufacture with a meaningful mechanistically-based relationship between in vitro and in vivo activity into development programs with the ability to withstand the rigorous tests of clinical evaluation rather than the further proof of concept [53].

CONCLUSION

Polysaccharide-coated mesoporous silica nanoparticles are a truly convergent system in which the structural precision of inorganic nanomaterial science and the biologically evolved properties of natural carbohydrate polymers feed into one another and when combined yield a system that is better than each individual component. In conclusion, the body of evidence presented here is clear that this convergence is not merely additive; indeed, chitosan and related polysaccharides do not merely protect a dissolving silica particle from the gastric acid, but rather transform the relationship of the nanoparticle to the gastrointestinal biological environment by regulating mucin adhesion, gating drug release at sub-organ level with anatomical accuracy, and transiently reconfiguring the epithelial tight junction complex in a reversible and physiologically acceptable way. These are soft skills that make polysaccharide-coated mesoporous silica superior to standard formulation methods and to mesoporous silica or polysaccharide alone. What the body of work to date has lacked — and is likely a major scientific need for the next generation of research — is a mechanistic connection between in vitro structural performance and in vivo pharmacokinetic response. However, the fact that a significant increase in dissolution in simulated fluids was only modestly reflected by an increase in systemic exposure in animal models does not reflect a failure of the platform, but rather a lack of understanding of the intestinal lumen dissolution kinetics of the drugs, as well as the coating behavior of the polysaccharide agents in the presence of physiological bile salts, and the quantitative relative importance of transcytosis versus paracellular transport in intact intestinal segments. The answer to these questions will be achieved by rigorously designed in situ perfusion studies and species appropriate IVIVC modeling that will decide if polysaccharide-coated mesoporous silica nanoparticles are a scientifically compelling but clinically unrealized technology, or if they can realize their demonstrated structural potential as programmable oral drug delivery platforms that address the bioavailability deficits of the next generation of poorly soluble and biologically sensitive therapeutics.

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