Multifunctional nanoparticle-reinforced tissue-derived hydrogel for accelerated healing of drug-resistant <em>Pseudomonas aeruginosa</em> infected wounds.

Chronic wounds complicated by multidrug-resistant bacterial infections pose a serious therapeutic challenge. Here, we develop an multifunctional hydrogel (PmB/Ag-PDA@ECM) by integrating silver nanoparticle-modified polydopamine (Ag-PDA) and polymyxin B (PmB) into a thermosensitive, pro-regenerative extracellular matrix (ECM) hydrogel. The hydrogel exhibits favorable physicochemical properties, including a porous microstructure (49.24% porosity), rapid swelling (~1068%), and strong tissue adhesion (6.24 kPa). Upon near-infrared (NIR) irradiation, it achieves mild photothermal heating (~50 °C), triggering synergistic antibacterial effects that completely eradicate polymyxin B-resistant <em>Pseudomonas aeruginosa</em> (PRPA). <em>In vitro</em>, the hydrogel promotes keratinocyte and endothelial cell proliferation and migration, while maintaining excellent cytocompatibility and hemocompatibility. In a PRPA-infected full-thickness wound model, the hydrogel rapidly sterilizes the wound bed and accelerates wound closure. Moreover, it effectively suppresses inflammation (reduced TNF-α, IL-6), promotes M2 macrophage polarization, and facilitates tissue remodeling, including neovascularization and regeneration of skin appendages. This work presents a clinically translatable hydrogel platform that simultaneously addresses antimicrobial resistance and supports high-quality tissue regeneration, offering a promising strategy for the treatment of complex infected wounds.