Neutrophil extracellular trap-inspired dynamic hydrogel with sonodynamic amplification for infected wound therapy

Infected skin wounds, particularly those complicated by mature biofilms and metabolically quiescent bacteria, often evade antibiotic monotherapy. Such challenging scenarios call for localized, resistance-resilient strategies that concurrently address pathogen eradication and tissue repair. Herein, we develop a neutrophil extracellular trap (NET)-inspired, ultrasound-responsive fibrous reticular dynamic hydrogel (POPP gel) that integrates bacterial enrichment/capture with sonodynamically amplified killing within an injectable matrix. Mildly cationic porphyrin-grafted poly(pyrimidine) nanoparticles (POPP NPs) are embedded in a dynamically crosslinked network of oxidized hyaluronic acid-phenylboronic acid (OHA-PBA), forming a nanofibrous reticular architecture with high interfacial exposure and adhesion toward LPS/polysaccharide-rich infectious microenvironments. Upon ultrasound activation, POPP NPs generate reactive oxygen species and synergize with charge-mediated membrane perturbation, enabling broad-spectrum bactericidal activity against Gram-negative and Gram-positive bacteria, including biofilm-embedded and drug-resistant phenotypes. The OHA-PBA network additionally confers shear-thinning injectability, rapid self-healing, wound-conforming coverage, and preserved fibroblast viability and migration. In murine full-thickness infected wounds and rat deep second-degree burn infections, ultrasound-activated POPP gel markedly reduces bacterial burden, accelerates wound closure, and promotes mature tissue reconstruction, characterized by continuous re-epithelialization, organized collagen deposition, and attenuated inflammation. Collectively, this NET-inspired sonodynamic hydrogel provides a modular design framework for localized antibacterial biomaterials aimed at refractory infected wounds. STATEMENT OF SIGNIFICANCE: Infected skin wounds with mature biofilms often resist antibiotics. Drawing inspiration from neutrophil extracellular traps, we develop an injectable sonodynamic hydrogel (POPP gel) that captures bacteria via a nanofibrous cationic network and kills them upon ultrasound activation. The gel also supports fibroblast function and wound healing. In murine infected wound and burn models, it reduces bacterial burden and accelerates tissue repair. This work offers a strategy for localized treatment of refractory infected wounds.