A Comprehensive Review on Engineering Release at the Molecular Level: Role of Functional Groups in Polysaccharide-Based Drug Delivery

Stimuli-responsive drug-delivery systems (SRDDS) have transformed precision medicine by enabling spatiotemporal control over therapeutic release, significantly reducing off-target toxicity while enhancing efficacy at the disease site. Naturally occurring polysaccharides, such as hyaluronic acid, chitosan, alginate, and dextran stand out as premier scaffolds for these “smart” nanoplatforms due to their inherent biocompatibility, biodegradability, and abundance of reactive sites for molecular engineering. This review explores the versatility of polysaccharide functionalization, detailing how the introduction of molecular “switches” allows these biopolymers to sense and respond to specific physiological triggers. We analyze the mechanisms behind acid–labile bonds for pH-triggered release, redox-sensitive bridges for intracellular delivery, and enzyme-cleavable sequences for bio-catalytic activation. By bridging the gap between molecular functionalization and clinical utility, these bio-responsive polysaccharide architectures enable integrated physiological monitoring and theranostic applications. This review highlights the impact of these advancements in overcoming biological barriers, providing a sophisticated blueprint for the next generation of nature-derived, “intelligent” biomaterials in cancer therapy.