Natural Polysaccharide-Based Biomaterials for Skin Wound Healing: Immunomodulatory Mechanisms and Macrophage M2 Polarization

Efficient cutaneous wound healing relies on the phenotypic transition of macrophages toward an anti-inflammatory, pro-reparative M2-like state. Non-healing chronic wounds are pathologically characterized by the breakdown of this polarization balance. In this review, we synthesize recent research on biomaterials fabricated from naturally occurring polysaccharides with intrinsic immunomodulatory activity, mainly represented by hydrogels that modulate macrophage phenotypic transitions. We first dissect the immune microenvironment of wound healing and elaborate on the core regulatory networks governing M1/M2 polarization, with a particular focus on signaling pathways and metabolic reprogramming. On this basis, we classify pro-M2 natural polysaccharides into mannose-containing and mannose-free categories according to their core structural motifs that mediate immunomodulatory activity, and detail their molecular mechanisms, including pattern recognition receptor engagement (MR, Dectin-1, CD44, etc.) and downstream signaling cascades (STAT6, PI3K/Akt, NF-κB, etc.). Representative polysaccharides such as konjac glucomannan (KGM), Ganoderma lucidum polysaccharide (GLP), chitosan (CS) and hyaluronic acid (HA) are discussed with a clarified structure–activity relationship (SAR). Finally, we highlight emerging design strategies for multi-functional immunomodulatory hydrogels, including mechano-biochemical coupling platforms and spatiotemporally controlled delivery systems, and analyze ongoing controversies and translational bottlenecks in this field. The relationship between material structure and function enables the rational design of purpose-built polysaccharide dressings that regulate immunity. This review highlights these materials as promising preclinical platforms for chronic wound management, although their clinical translation requires further validation.