Advances in Bioactive Polysaccharide-Small-Molecule Drug Supramolecular Nanocomplexes for Drug Delivery and Therapeutic Applications.

Bioactive polysaccharides (e.g., fucoidan, β-glucans, and medicinal plant polysaccharides) contain functional groups that interact with drug molecules, and some also retain their own biological activities. Through reversible noncovalent interactions, they can associate with small-molecule drugs and form supramolecular nanocomplexes, defined here as nanoscale assemblies in which the polysaccharide is a main structural component and its association with the drug contributes to assembly or drug retention. Multicomponent composites and bulk local matrices are discussed separately as related or extended systems. The review covers hydrogen bonding, hydrophobic association, electrostatic complexation, π-π stacking, and the cooperation among these interactions, together with the effects of pH, ionic strength, concentration, and solvent composition. Nanoprecipitation/solvent exchange, polyelectrolyte complexation, direct aqueous self-assembly, and microfluidic-assisted assembly are compared with respect to nanostructure formation, process control, and reproducibility. Molecular, colloidal, solid-state, and computational evidence is examined together when interpreting structure-assembly-performance relationships. Reported advantages include improved drug dispersibility, colloidal stability, release control, bioavailability, cellular uptake, biodistribution, and safety. In some systems, the polysaccharide itself may also contribute to therapeutic effects in tumors, inflammatory diseases, and wound healing. Related local-matrix systems are considered separately. Further development of these nanocomplexes will require better quantitative analysis of assembly mechanisms, more consistent polysaccharide characterization, careful biocompatibility assessment, scalable preparation, and longer-term safety evaluation.