Zinc-Containing Bioactive Glass Programs Macrophage Polarization through Extracellular Traps Regulation for Enhanced Diabetic Wound Healing.

Abstract

Impaired diabetic wound healing is driven by immune dysregulation and microenvironmental disruptions induced by hyperglycemia, leading to excessive inflammation and defective macrophage polarization. Although macrophage extracellular traps (METs) play critical roles in chronic inflammatory diseases, their involvement in shaping the diabetic wound immune microenvironment and impeding macrophage polarization remains insufficiently understood. Here, we present zinc-containing bioactive glass (ZnBG), in which zinc incorporation confers immunomodulatory properties. In a type 2 diabetic full-thickness skin excision model, ZnBG significantly mitigates MET-associated oxidative stress and inflammation. Mechanistic investigations reveal that ZnBG effectively suppresses MET formation by reducing reactive oxygen species levels, inhibiting PAD4 activation, and blocking the NLRP3/caspase-1/GSDMD signaling pathway. Consequently, ZnBG facilitates macrophage transition from the pro-inflammatory M1 phenotype to the reparative M2 phenotype in diabetic wounds, thereby alleviating inflammation, enhancing neovascularization, and ultimately promoting diabetic wound healing. These findings provide an innovative therapeutic strategy that integrates ZnBG with targeted modulation of macrophage function for the treatment of diabetic wounds.