Chemically modified polysaccharides: A review of structure-activity relationships and mechanisms for enhanced...

Polysaccharides are abundant natural macromolecules; however, despite their widespread occurrence, their practical applications remain limited, primarily due to unfavorable physicochemical properties and relatively low bioactivity. Chemical modification has emerged as a promising strategy to tailor the physicochemical properties of polysaccharides and enhance their biological performance beyond that of native polysaccharides, thereby expanding their therapeutic and nutraceutical applications. Despite growing research interest, a systematic synthesis of structure-activity relationships and the molecular mechanisms governing modified polysaccharides remains lacking. This review addresses this critical gap by synthesizing findings from over 200 peer-reviewed publications published over the past decade, with a specific focus on five major modification strategies: carboxymethylation, sulfation, phosphorylation, acetylation, and selenylation. Degradation-based approaches, including chemical, physical, and enzymatic methods, are excluded from the scope of this review. Available evidence indicates that these modifications generally enhance a range of pharmacological activities, including antioxidant, immunomodulatory, anti-inflammatory, antineoplastic, hypoglycemic, and hypolipidemic effects. Although bioactivity is primarily governed by the substituent type and the degree of substitution, these variables rarely exhibit simple linear relationships. Mechanistically, these effects are mediated through direct interactions with biological targets, modulation of key signaling pathways, and regulation of enzyme activity and gene expression. To facilitate translation advancement, future studies should prioritize targeted molecular design, evaluation of oral bioavailability, comprehensive toxicological assessment, deeper mechanistic elucidation, stringent quality control, and the exploration of synergistic combination strategies.