Structure-function paradigms of natural polysaccharides in hepatocellular carcinoma therapy.

Hepatocellular carcinoma (HCC) is a major cause of cancer mortality worldwide, and its limited response to conventional chemotherapeutics underscores the need for safer, multifunctional approaches. Natural polysaccharides, complex carbohydrates derived from plants, fungi, algae, animals, and bacteria, represent a structurally diverse class of bioactive macromolecules that combine therapeutic and material properties. Their monosaccharide composition, linkage types, branching patterns, molecular weights, and charge densities determine receptor recognition, intracellular trafficking, and signaling modulation. Plant-derived polysaccharides act through asialoglycoprotein receptor engagement when galactose-rich motifs are present, alongside oxidative-stress regulation and microRNA control; fungal β-glucans engage Toll-like receptor and Dectin-1 pathways to activate immunity and sensitize tumor cells; algal fucoidans and carrageenans inhibit angiogenesis and metastasis through sulfate- and uronic-acid-dependent signaling; animal polysaccharides such as hyaluronic acid and chitosan provide CD44-targeted delivery and stromal modulation; and bacterial exopolysaccharides trigger apoptosis via charge- and topology-dependent mitochondrial collapse. Together, these systems reveal a unified structure-function paradigm that links chemical geometry to biological outcomes. Advances in derivatization, nanocarrier development, and glycomics now enable the predictive design of polysaccharide-based therapeutics with reproducible activity and reduced toxicity. This review integrates mechanistic, structural, and translational perspectives to position polysaccharides as designable molecular platforms for targeted and synergistic intervention in HCC.