Engineered neuro-vascular coupling and immunomodulation accelerates diabetic wound healing with a NO/O2-releasing cascade nanozyme hydrogel.

The complex pathologic microenvironment of diabetic wounds-characterized by impaired angiogenesis, neuropathy, bacterial infection, and immune dysfunction-severely disrupts the normal healing process. This study presents a cascade nanozyme hydrogel dressing that releases nitric oxide (NO) and oxygen (O2) to enhance neuro-vascular coupling and immunomodulation for accelerated diabetic wound repair. The hydrogel was rapidly formed under UV illumination, integrating dopamine-modified gelatin (Gel-DA) and quaternary ammonium-lipoic acid-modified chitosan (LQCS) as an adhesive matrix, alongside Cu/Mg-tannic acid nanozymes loaded with the NO donor BNN6 (PTA-Cu-Mg/BNN6) as the functional core. In this design, the Gel-DA and LQCS matrix provides excellent tissue adhesion and inherent antibacterial capability, while the PTA-Cu-Mg/BNN6 nanozymes enable near-infrared (NIR)-triggered NO release and catalase-like decomposition of endogenous H2O2 for sustained O2 generation. Under NIR irradiation, the simultaneous release of NO and O2 from the hydrogel demonstrated effective antibacterial activity, promoted macrophage polarization toward the M2 phenotype, enhanced endothelial cell proliferation and angiogenic gene expression, and facilitated neurite outgrowth. In vivo results confirmed that the hydrogel significantly accelerated the healing of infected diabetic wounds by eradicating bacteria, modulating the immune microenvironment, and synergistically promoting angiogenesis and nerve regeneration. This easily fabricated NO/O2-releasing cascade nanozyme hydrogel represents a promising therapeutic strategy with great potential for clinical translation.