Polysaccharide Reengineering: Strategic Modifications and Biofunctional Outcomes of Natural Polysaccharides

Natural polysaccharides have attracted considerable interest in pharmaceutical and biomedical applications. However, native polysaccharides often possess limitations, like poor solubility, inadequate mechanical strength, limited stability, and insufficient control over their functional and biological properties. Consequently, structural modification and function-driven reengineering of natural polysaccharides have emerged as important strategies for tailoring the physicochemical and biological characteristics to meet the requirements of advanced pharmaceutical and biomedical systems. Beyond individual modification strategies, polysaccharide reengineering provides a design-oriented framework in which structural features are deliberately tuned to establish relationships between molecular or network architecture, physicochemical properties, biointerfacial interactions, and biological function. This review examines polysaccharide reengineering as a function-driven approach to tailoring the structure and performance of natural polysaccharides. Rather than simply cataloguing modification methods, the review critically connects principal reengineering strategies, including carboxymethylation, sulfation, phosphorylation, grafting, and interpenetrating polymer network (IPN) formation, with their effects on structural characteristics, physicochemical properties, biointerfacial interactions, biological functions, and pharmaceutical performance. Particular emphasis is placed on identifying structure–property–biofunction relationships and on extracting design principles that can guide the selection and combination of reengineering strategies for specific applications. Reengineering of natural polysaccharides provides a versatile strategy to overcome the inherent limitations of native materials and to develop polysaccharide-based platforms with tailored physicochemical and biological properties. Different modification approaches offer distinct functional advantages: carboxymethylation can improve hydrophilicity and pH-responsive swelling, whereas sulfation and phosphorylation introduce anionic functionalities that modulate charge-dependent interactions and biological responses. Similarly, grafting and interpenetrating polymer network (IPN) formation provide greater control over mechanical strength, swelling, stability, drug-loading capacity, and controlled-release behavior. Collectively, these findings demonstrate that the performance of reengineered polysaccharides is determined not by the modification strategy alone, but by the combined effects of the resulting molecular structure, physicochemical characteristics, and interactions with biological environments. Despite these advances, the development of predictable structure-function relationships remains challenging because of variations in polysaccharide source, molecular weight, degree and distribution of modification, and characterization methodologies. Therefore, future research should shift from empirical modification toward rational, function-driven polysaccharide reengineering, in which structural parameters are deliberately controlled to achieve predefined material and biological outcomes.