Polysaccharide-based drug conjugates and related delivery systems for Alzheimer's disease: from molecular design to translational challenges.

Alzheimer's disease (AD) presents distinct extracellular, intracellular and vascular delivery targets, yet brain exposure of candidate therapeutics remains difficult to establish. This narrative review compares hyaluronic acid, chitosan, cyclodextrin, dextran, alginate and pectin systems by construct architecture, route, blood-brain barrier (BBB) evidence, cargo release and biological response. The literature includes covalent drug conjugates, loaded or coated carriers, host-guest complexes and intrinsically active polymers; evidence from one category cannot validate another. Clinical programs involving intravenous hydroxypropyl-β-cyclodextrin and a transferrin-receptor antibody shuttle provide context, but do not establish BBB transport for the conjugates reviewed. We examine how polymer size and degradation influence immune safety, particularly chitosan-associated NLRP3 activation and context-dependent responses to hyaluronic acid fragments. We distinguish endothelial or whole-brain signal from parenchymal active-drug exposure, and discuss payload-specific endosomal escape. Advancement requires a defined construct, quantitative target-site exposure, target engagement, comparison with free drug and a matched carrier, and route-appropriate safety data.