A sprayable TQ/Ce6@SAB/F-gel for accelerating wound healing via hypoxia-tolerant photodynamic therapy and immune-metabolic pathway.

Abstract

Chronic diabetic wounds are characterized by hypoxia, persistent microbial infection, and impaired healing, posing significant challenges to conventional therapies. Herein, we present a novel sprayable double-network hydrogel platform designed to achieve efficient antimicrobial activity and accelerated wound repair under hypoxic conditions by leveraging a type I photodynamic therapy (PDT) and immune-metabolic regulatory strategy. Specifically, we employ salvianolic acid B (SAB) to form a self-assembled hydrogel (SAB-gel) and incorporate fibrin to construct a robust and acidic double-network SAB/F-gel with enhanced mechanical strength and acidic environment. Concurrently, thymoquinone (TQ) and chlorin e6 (Ce6) are self-assembled via hydrophobic interactions to form TQ/Ce6 nanoparticles (TQ/Ce6 NPs) and embedded in the SAB/F-gel, to fabricate the TQ/Ce6@SAB/F-gel. Under low-oxygen conditions, TQ acts as an electron-transfer mediator, enabling Ce6 to generate abundant superoxide anions (·O₂^-) via type I PDT under red light (RL) irradiation. These ·O₂^- are subsequently converted into hydrogen peroxide (H₂O₂) and hydroxyl radicals (·OH) in the acidic environment provided by acidic SAB/F-gel, thereby reducing the dependence on oxygen and maintaining potent antimicrobial efficacy against MRSA, Pseudomonas aeruginosa (Pa), Acinetobacter baumannii (Ab), Escherichia coli (E. coli) and Candida albicans (Ca). In vitro experiments demonstrated that TQ/Ce6@SAB/F-gel regulates macrophage M2 polarization and promotes endothelial cell proliferation, migration, and tube formation via the immune-metabolic regulatory pathways. When applied to MRSA-infected diabetic wounds in mice, the hydrogel in combination with RL completely eradicated bacteria, promoted collagen deposition and angiogenesis, and significantly accelerated wound closure, as demonstrated by histological examination and transcriptome sequencing. This work offers a versatile, biocompatible, and oxygen-independent PDT-based hydrogel system for the treatment of refractory infected diabetic wounds, offering potential for clinical translation and improved patient outcomes.