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

Oral bioavailability enhancement of poorly water-soluble drugs remains one of the most persistent and pharmacoeconomically significant challenges in pharmaceutical development, with estimates indicating that up to 90% of new molecular entities belong to BCS Classes II and IV. Mesoporous silica nanoparticles have emerged as structurally distinctive inorganic carriers capable of stabilizing crystalline drugs in an amorphous state through nanopore confinement, substantially improving dissolution rate and apparent solubility. However, bare silica surfaces lack the biological responsiveness, mucoadhesive capacity, and stimulus-controlled drug gating required to fully exploit the pharmacokinetic potential of this platform in the gastrointestinal environment. Polysaccharide surface functionalization principally through chitosan, alginate, hyaluronic acid, and their derivatives addresses these limitations by introducing pH-responsive, enzyme-triggered, and redox-activated release mechanisms while simultaneously enabling reversible tight junction modulation and mucin-mediated adhesion at the intestinal epithelium. This review examines the structural diversity of mesoporous silica architectures relevant to oral delivery, the chemistry and stability consequences of three principal coating strategies, the sequential gastrointestinal barrier evasion mechanisms operative in polysaccharide-coated systems, in vivo pharmacokinetic evidence across BCS drug classes, integration into solid oral dosage forms, and the safety and regulatory considerations governing clinical translation. Collectively, the evidence positions polysaccharide-coated mesoporous silica nanoparticles as a modular, biologically responsive oral drug delivery platform whose translational realization depends on convergence between reproducible manufacturing, mechanistic pharmacokinetic characterization, and regulatory-aligned safety frameworks