Sulfated polysaccharide facilitates macrophage-Treg crosstalk to mitigate chronic inflammation in diabetic wound healing

Diabetic wounds struggle to heal due to chronic inflammation and immune dysregulation, in which regulatory T cells (Tregs) are critical for inflammation resolution and tissue repair. However, effective strategies for on-demand Treg recruitment remain elusive. Here, we innovatively integrated sulfated chitosan (SCS)—a chemically modified polysaccharide—with a microneedle structure to engineer an active immunomodulatory delivery system. The engineered sulfation domains confer synergistic cytokine-binding capacity to SCS, thereby equipping the material with enhanced functionality in immunomodulation. Mechanistically, SCS drives macrophage polarization via the IL-4/STAT6-PPARγ cascade, triggering CCL22-dependent Treg chemotaxis. The SCS establishes bidirectional macrophage-Treg crosstalk, enabling self-sustaining inflammation resolution through M2 phenotype stabilization and Treg-mediated feedback loops. This biomaterial-driven coordination between innate and adaptive immunity surpasses passive drug delivery approaches, effectively reducing inflammation and promoting wound healing without the need for exogenous biologics. Our work pioneers endogenous immunity harnessing through biomaterial design, offering a paradigm shift for diabetic wound therapeutics. • Macrophages-Tregs crosstalk critically regulates chronic inflammation in diabetic wounds. • Sulfated chitosan activates IL-4/STAT6-PPARγ, inducing M2 macrophages to secrete CCL22 and recruit Tregs. • Tregs aid wound healing by promoting epidermal regeneration and neovascularization, and by maintaining M2 polarization.