Abstract

Chronic diabetic wounds present a critical clinical challenge due to persistent inflammation and compromised healing. Here, we report a sprayable nanozyme hydrogel that epigenetically remodels macrophages (Mφ) to suppress inflammation and coordinate regeneration. Ultrasmall copper-based nanozymes (CuNZ, ~4 nm) synthesized via an eco-friendly one-pot method demonstrated potent multi-radical scavenging activity. When integrated into gelatin methacryloyl (Gel), CuNZ@Gel exhibited sprayability, conformal skin coverage, and storage stability, offering potential for clinical translation. Notably, the nanozyme hydrogel induced distinct epigenetic modifications in Mφ by remodeling chromatin accessibility, thereby shifting gene expression from a pro-inflammatory to an anti-inflammatory profile. This epigenetic modulation sustained under oxidative stress, actively suppressing inflammation while facilitating regenerative responses. In rat diabetic wound models, CuNZ@Gel significantly accelerated healing through its coordinated antioxidant, anti-inflammatory, and pro-regenerative actions. Unlike conventional passive dressings, this sprayable nanozyme hydrogel proactively remodels the wound microenvironment via epigenetic control of inflammation, providing a promising therapeutic strategy for managing chronic diabetic wounds and inflammatory skin complications.