Coordination-based Nanocomposite Hydrogel Promotes Tissue Regeneration Under Infection-Compromised Conditions

Abstract Impaired tissue regeneration, rather than mere bacterial colonization, represents the core pathological challenge in infected wounds, where persistent infection, biofilm formation, and inflammatory dysregulation collectively disrupt the healing process. Herein, we report a coordination-based nanocomposite hydrogel (DAP-Cu NGs) designed to restore regenerative capacity by integrating infection control with active microenvironmental remodeling. The system comprises daphnetin-copper nanoparticles (DAP-Cu NPs) self-assembled via coordination chemistry and loaded into a poloxamer thermosensitive hydrogel. This design achieves two key objectives: nanoconfinement of Cu2+ to mitigate cytotoxicity, and pH-responsive release enabling spatiotemporally controlled drug delivery within the acidic infection microenvironment. Beyond synergistic elimination of pathogens and biofilms, DAP-Cu NGs actively modulate the regenerative niche by inducing macrophage polarization toward the pro-repair M2 phenotype, promoting keratinocyte and fibroblast migration, and enhancing angiogenesis with orderly collagen deposition. In an infected wound model, DAP-Cu NGs significantly accelerated wound closure and achieved near-complete tissue reconstruction with favorable biocompatibility. Critically, these regenerative outcomes were accomplished without exogenous growth factors, highlighting the inherent bioactivity of the coordination platform. This work establishes a paradigm shift from passive antimicrobial therapy toward active regeneration-engaging biomaterials, positioning infection control as an enabling step rather than a therapeutic endpoint for treating infection-compromised wounds.