An infection-responsive multifunctional hydrogel enables potent activity against methicillin-resistant Staphylococcus aureus and promotes wound healing

Infected wounds remain a significant clinical challenge due to bacterial resistance and impaired healing. Therefore, developing effective antibacterial agents and precise delivery systems is crucial for rapid wound repair. To address this, we constructed zeolitic imidazolate framework-8 (ZIF-8) nanoparticles loaded with the host defense peptide-mimicking glycine-poly(2-oxazoline) (Gly-POX) and incorporated them into methacrylated gelatin (GelMA) to prepare the Gel-P@Z nanocomposite hydrogel. The hydrogel integrates the following core design elements: the pH-responsive degradation of ZIF-8 enables targeted drug release within the infected microenvironment; Gly-POX, mimicking the structure of host defense peptides, exerts membrane-disruptive antibacterial activity against MRSA, which possesses a negatively charged cell membrane, through its positively charged side chains; and the GelMA hydrogel provides a three-dimensional extracellular matrix-like scaffold that supports cell adhesion and proliferation. Gel-P@Z exhibited a slow and sustained release of Gly-POX and achieved >99% antibacterial efficacy against drug-resistant bacteria without toxicity. Moreover, Gel-P@Z promoted macrophage polarization from M1 to M2 phenotype and enhanced efferocytosis, while also facilitating fibroblast migration and inducing contraction in ex vivo fascia explants. In a murine full-thickness MRSA-infected wound model, Gel-P@Z effectively cleared bacteria, modulated the inflammatory microenvironment, and promoted both angiogenesis and collagen deposition. RNA-seq analysis revealed that Gel-P@Z accelerates healing via upregulation of the TGF-β signaling pathway, driving fibroblast-to-myofibroblast transition and promoting tissue fibrosis. This work not only proposes a novel strategy for antibacterial polymer delivery but also offers a promising solution for the management of infected wounds.