Nanozyme-crosslinked dual-network hydrogel enables multi-stage modulation of the dysregulated repair cascade for regenerative wound healing.

Abstract

Adult mammalian wound healing typically results in fibrosis-associated repair rather than regenerative restoration, a process that can be further exacerbated by persistent inflammation, microbial infection, and aberrant mechanotransduction. Here, we present a nanozyme-crosslinked dual-network hydrogel (GPP@VP) that enables multi-stage modulation of this dysregulated repair cascade. The hydrogel integrates a dynamic γ-polyglutamic acid (γ-PGA)/ε-poly-L-lysine (ε-PLL) ionic network with CaP@TGnase-mediated covalent crosslinking, providing mechanical robustness, injectability, and wet-tissue adhesion. Functionally, GPP@VP enables stage-associated regulation across the healing process: Ca²⁺ release promotes rapid hemostasis at early stages; ε-PLL provides intrinsic bacteriostasis, while verteporfin (VP) enables on-demand photodynamic antibacterial activity under near-infrared (NIR) irradiation; and subsequent modulation of macrophage polarization and mechanotransduction pathways attenuates fibroblast activation and excessive extracellular matrix deposition. <i>In vivo</i>, GPP@VP demonstrated consistent efficacy across methicillin-resistant <i>Staphylococcus aureus</i> (MRSA)-infected burn wounds, a rabbit ear scar model, and postoperative adhesion models, with reduced inflammation, improved tissue remodeling, and a shift toward regenerative healing. Transcriptomic analysis further revealed coordinated regulation of immune and extracellular matrix (ECM)-related pathways. This work highlights a material strategy that enables coordinated modulation of the dysregulated repair cascade, providing a promising approach toward regenerative wound healing.