Structural-activity relationship of Lycium barbarum polysaccharides in immunomodulation: integrating molecular insights with target identification for therapeutic development

The immunomodulatory potential of <i>Lycium barbarum</i> polysaccharides (LBP) is well-established, yet the intricate structure-activity relationships (SAR) underlying these effects require clarification to advance therapeutic applications. This review synthesizes current knowledge on how specific structural parameters of LBP, including molecular weight, monosaccharide composition, glycosidic linkage types, and chemical modifications influence its immunoregulatory functions. Key findings reveal a non-linear dependence of LBP's immunomodulatory activity on molecular weight. Fractions within the medium molecular weight range (10⁵-10⁶ Da) often demonstrate optimal efficacy, which is attributed to their capacity for facilitating multivalent binding to pattern recognition receptors (PRRs). Furthermore, a high content of arabinose and galactose is a critical structural determinant, with arabinogalactan-like motifs serving as key recognition elements for immune cell activation. Mechanistically, LBP orchestrates immune responses through multi-target pathways. It directly modulates macrophage polarization via the STAT1/STAT6 pathways, promotes dendritic cell maturation through NF-κB and Notch signaling, and influences T-cell differentiation. Concurrently, LBP exerts indirect immunomodulatory effects via the gut microbiota-immune axis by enriching beneficial bacteria and their immunoregulatory metabolites, such as short-chain fatty acids. Despite robust preclinical evidence, clinical translation is hampered by the heterogeneity of LBP preparations. This review underscores the necessity of standardizing LBP based on SAR insights to develop precision immunomodulators for therapeutic applications.