Functional hydrogels promote chronic infectious wound healing by re-rousing macrophage M1 and inducing bacterial copper-like death

Abstract

Traditional antibiotics are often ineffective against biofilm-associated infections, and biofilm-induced macrophage immune evasion directly halts the wound healing process. Disrupting biofilms and regulating macrophage immune functions are critical to improving wound healing. In this study, we synthesized g-C 3 N 4 with peroxidase (POD) enzyme activity via thermal polymerization and copper alginate microspheres (CAM) via gas cutting. These were co-encapsulated into GelMA hydrogels to form a functionalized wound repair system (GelMA/CAM@g-C 3 N 4 ) with both anti-biofilm and local immune microenvironment remodeling capabilities. In vitro, this system exhibited excellent biocompatibility and promoted endothelial cell migration, vascular formation, and CD31 expression. It also polarized macrophages toward the M1 phenotype, restoring their pro-inflammatory functions, upregulating inflammatory cytokines (IL-1, IL-6, TNF-α), and inhibiting Staphylococcus aureus and Escherichia coli . In vivo, the system suppressed S. aureus growth, promoted angiogenesis and collagen deposition, and reshaped the pathological microenvironment to achieve wound repair and regeneration. Conclusions: This system offers a new therapeutic strategy for chronic infectious wounds. • Based on the formation of biofilm that led to immune evasion of macrophages, we simulated the enzyme activity of POD with g-C 3 N 4 to successfully re-rousing the M1 phenotype of macrophages. • Functionalized hydrogel microspheres sustained the long-term release of copper ions to achieve continuous antibacterial activity for infected wounds and promoted angiogenesis. • The system induced a copper-like death in bacteria by interfering with bacterial membrane functions, biosynthesis, energy metabolism, and the generation of purines and pyrimidines.

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