A nanoenzyme-modified hydrogel targets macrophage reprogramming-angiogenesis crosstalk to boost diabetic wound repair. This study presents a novel hydrogel, CeO₂-Y@ZIF-8@Gel, designed to enhance diabetic wound healing by targeting the interplay between macrophage reprogramming and angiogenesis. The hydrogel integrates antibacterial and anti-inflammatory properties with wound adaptability. It contains CeO₂, a nanoenzyme with superoxide dismutase and catalase activities, which scavenges reactive oxygen species (ROS) to limit mitochondrial damage, and Y-27632, a ROCK inhibitor that repairs mitochondrial DNA and reduces cell apoptosis. The hydrogel is encapsulated in a photocross-linkable hydrogel (GelMA) with cationic quaternary ammonium salt groups, providing antibacterial properties. CeO₂-Y@ZIF-8@Gel reduces the leakage of oxidatively damaged mitochondrial DNA (Ox-mtDNA), which activates the cGAS-STING pathway, leading to M2 macrophage polarization and anti-inflammatory factors. This modulation of the crosstalk between macrophage reprogramming and angiogenesis alleviates inflammation in the microenvironment and accelerates wound healing. The hydrogel effectively scavenges ROS, reduces oxidative stress, and promotes vascularization, enhancing the repair of diabetic wounds. In vivo experiments showed that CeO₂-Y@ZIF-8@Gel significantly accelerated wound healing, reduced inflammation, and improved the microenvironment. The hydrogel's ability to regulate the NLRP3 pathway and cGAS-STING pathway, as well as its anti-inflammatory effects, makes it a promising treatment for diabetic wounds. The study highlights the potential of this hydrogel in non-surgical treatments for diabetic wounds by modulating multiple mechanisms in signal transduction and achieving immunoregulation between endothelial cells and macrophages.A nanoenzyme-modified hydrogel targets macrophage reprogramming-angiogenesis crosstalk to boost diabetic wound repair. This study presents a novel hydrogel, CeO₂-Y@ZIF-8@Gel, designed to enhance diabetic wound healing by targeting the interplay between macrophage reprogramming and angiogenesis. The hydrogel integrates antibacterial and anti-inflammatory properties with wound adaptability. It contains CeO₂, a nanoenzyme with superoxide dismutase and catalase activities, which scavenges reactive oxygen species (ROS) to limit mitochondrial damage, and Y-27632, a ROCK inhibitor that repairs mitochondrial DNA and reduces cell apoptosis. The hydrogel is encapsulated in a photocross-linkable hydrogel (GelMA) with cationic quaternary ammonium salt groups, providing antibacterial properties. CeO₂-Y@ZIF-8@Gel reduces the leakage of oxidatively damaged mitochondrial DNA (Ox-mtDNA), which activates the cGAS-STING pathway, leading to M2 macrophage polarization and anti-inflammatory factors. This modulation of the crosstalk between macrophage reprogramming and angiogenesis alleviates inflammation in the microenvironment and accelerates wound healing. The hydrogel effectively scavenges ROS, reduces oxidative stress, and promotes vascularization, enhancing the repair of diabetic wounds. In vivo experiments showed that CeO₂-Y@ZIF-8@Gel significantly accelerated wound healing, reduced inflammation, and improved the microenvironment. The hydrogel's ability to regulate the NLRP3 pathway and cGAS-STING pathway, as well as its anti-inflammatory effects, makes it a promising treatment for diabetic wounds. The study highlights the potential of this hydrogel in non-surgical treatments for diabetic wounds by modulating multiple mechanisms in signal transduction and achieving immunoregulation between endothelial cells and macrophages.