Advanced Fe-COF-based photothermal cascade nano-generator for sterilization and promoting wound healing

•Controlled release of low-dose of NO through cascade reactions from Fe-COF NRs.•Synergistic PTT/PDT antibacterial therapy and NO-based gas therapy strategy was obtained.•Promoting diabetic wound healing by Fe-COF NRs through enhancing angiogenesis. Pharmacological treatments of diabetic ulcers remain a huge challenge due to the impaired angiogenesis and uncontrolled bacterial infection. Here, iminopyrazine-based Fe-covalent organic frameworks (Fe-COF) were synthesized via a subcomponent assembly strategy, and functionalized through covalent modification of L-arginine and encapsulated with photosensitizer IR780 and hyaluronic acid for enhancing diabetic wound healing. The functionalized Fe-COF (Fe-COF NRs) showed peroxidase-like activity and near-infrared (NIR)-controlled NO generation property, which can be used for synergistic photothermal/photodynamic antibacterial therapy and NO-based gas therapy. Treatment with Fe-COF NRs + NIR caused pathogenic elimination and enhanced angiogenesis, subsequently leading to accelerated wound healing in a rat model of infected diabetic wound. Mechanistically, the results from RNA sequencing analysis indicated that Fe-COF NRs treatment significantly induced the expression of genes involved in angiogenesis, but obviously inhibited the expression of proinflammatory cytokines. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that collagen-containing extracellular matrix, hair follicle development, PI3K-Akt signaling pathway, wound healing and skin development were significantly enriched after Fe-COF NRs treatment. Taken together, Fe-COF NRs provide a novel therapeutic strategy for the treatment of infected diabetic wound.