A nanoenzyme-modified hydrogel targets macrophage reprogramming-angiogenesis crosstalk to boost diabetic wound repair

Diabetic wounds has a gradually increasing incidence and morbidity. Excessive inflammation due to immune imbalance leads to delayed wound healing. Here, we reveal the interconnection between activation of the NLRP3 inflammatory pathway in endotheliocyte and polarization of macrophages via the cGAS-STING pathway in the oxidative microenvironment. To enhance the immune-regulation based on repairing mitochondrial oxidative damage, a zeolitic imidazolate framework-8 coated with cerium dioxide that carries Rhoassociated protein kinase inhibition Y-27632 (CeO₂–Y@ZIF-8) is developed. It is encapsulated in a photocross-linkable hydrogel (GelMA) with cationic quaternary ammonium salt groups modified to endow the antibacterial properties (CeO₂–Y@ZIF-8@Gel). CeO₂ with superoxide dismutase and catalase activities can remove excess reactive oxygen species to limit mitochondrial damage and Y-27632 can repair damaged mitochondrial DNA, thus improving the proliferation of endotheliocyte. After endotheliocyte uptakes CeO₂–Y@ZIF-8 NPs to degrade peroxides into water and oxygen in cells and mitochondria, NLRP3 inflammatory pathway is inhibited and the leakage of oxidatively damaged mitochondrial DNA (Ox-mtDNA, a damage-associated molecular pattern) through mPTP decreases. Futhermore, as the cGAS-STING pathway activated by Ox-mtDNA down-regulated, the M2 phenotype polarization and anti-inflammatory factors increase. Collectively, CeO₂–Y@ZIF-8@Gel, through remodulating the crosstalk between macrophage reprogramming and angiogenesis to alleviate inflammation in the microenvironment and accelerates wound healing.