A Bioresponsive Hydrogel Remodels the Hypoxic-Immune Microenvironment via Synergistic Phototherapy for Chronic Wound Regeneration.

Abstract

Chronic refractory wounds, pose significant clinical challenges due to their complex pathological features including persistent hypoxia, persistent bacterial infection, dysregulated immunity, and impaired angiogenesis. To overcome conventional therapeutic limitations, a pH/temperature-responsive dual-network hydrogel (APIC@Gel) is engineered by integrating an antimicrobial nanoplatform (AuNRs@PF127@ICG@Cat) into gels consisting of carboxymethyl chitosan (CMC) and Pluronic 127 (F127), featuring dynamically crosslinked covalent/physical networks that enable spatiotemporally controlled drug release. Under monochromatic near-infrared irradiation, the hydrogel synchronizes photodynamic/photothermal actions, where reactive oxygen species oxidizes biofilm polysaccharides and depletes bacterial nicotinamide adenine dinucleotide, while cationic surface of CMC further destabilizes pathogen membranes. Simultaneously, catalase-mediated conversion of wound-derived hydrogen peroxide into O₂ alleviates hypoxia, creating a regenerative microenvironment. The sustained O₂ supply further promotes M2 macrophage polarization, stimulates angiogenesis through the PI3K/Akt pathway, mitigates chronic inflammation, and advances vascular regeneration. Animal experiments demonstrate that APIC@Gel demonstrates excellent therapeutic effect in accelerating wound healing in mice infected with Staphylococcus aureus. By dynamically coordinating infection control, hypoxia mitigation, immunomodulation, and neovascularization, this bioresponsive hydrogel accelerates wound repair through adaptive interactions with the evolving wound microenvironment, offering a transformative strategy for chronic wound healing.