From nature to clinic: Lessons from successfully marketed polysaccharide drugs

Natural polysaccharides have emerged as promising drug candidates due to their excellent biocompatibility, multi-target actions, and low toxicity. However, despite abundant research, few have achieved market approval globally, revealing a significant translational gap. This review systematically examines natural polysaccharide drugs approved by regulatory agencies worldwide (excluding dietary supplements and excipients). Through analysis of successful examples including heparin, lentinan, polysaccharide-K (PSK), and hyaluronic acid, we identify key success factors: (1) structural clarity exists on a continuum from complete sequence-level definition (heparin) to characteristic structural units (lentinan), with variations across regulatory regions; (2) mechanisms of action require identification of 1-2 primary receptors/targets rather than vague multi-target descriptions; (3) quality control necessitates a three-dimensional system integrating chemical indicators, structural features, and biological activities; (4) administration routes predominantly involve injection/local delivery, as oral bioavailability remains challenging; (5) clinical positioning focuses on adjuvant therapy rather than monotherapy. Analysis suggests that Western agencies (FDA/EMA) demand complete structural characterization and clearly defined mechanisms, while East Asian regions accept characteristic structures combined with clinical evidence. This review proposes targeted solutions for three critical bottlenecks-standardization and quality control, mechanistic understanding, and bioavailability-providing actionable development pathways for natural polysaccharide drug candidates.