Sprayable Nanozyme Hydrogel Epigenetically Reprograms Inflammation for Diabetic Wound Regeneration [Chip-seq]

Chronic diabetic wounds present a critical clinical challenge due to persistent inflammation and compromised healing. Here we report a novel sprayable nanozyme hydrogel that epigenetically reprograms macrophages 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 excellent sprayability, conformal skin coverage, and long-term storage stability, offering substantial translatable potential. Notably, the nanozyme hydrogel induced distinct epigenetic modifications in macrophages by remodeling chromatin accessibility, effectively shifting gene expression from pro-inflammatory to anti-inflammatory profiles. This epigenetic modulation persisted under oxidative stress, actively suppressing inflammatory while facilitating regenerative responses. In diabetic wound models, CuNZ@Gel significantly accelerated healing through its coordinated antioxidant, anti-inflammatory, and pro-regenerative actions. Unlike conventional passive dressings, our sprayable nanozyme hydrogel proactively reprograms the wound microenvironment via epigenetic antioxidant mechanisms, offering novel insights and strategy for managing chronic diabetic wounds and inflammatory skin complications.