Macrophage‐Targeted Nanozyme Interrupts Inflammation‐Oxidative Stress Storm in Diabetic Wound Healing

ABSTRACT Unhealed diabetic skin wounds may cause infections, tissue necrosis, and even amputation. The activated macrophages‐mediated inflammation‐oxidative stress storm seriously hindered diabetic wound healing. However, currently available anti‐inflammatory and antioxidative drugs have limited efficacy due to non‐continuous activity and poor accumulation within activated macrophages. Herein, a novel Cu‐based metal‐organic framework (Cu‐MOF) was coated with dextran sulfate (DSS) to develop an activated macrophage‐targeted CuMD nanozyme. Such CuMD nanozymes exhibit excellent activated macrophage targeting ability via the specific binding between DSS and macrophage scavenger receptor A. And CuMD nanozyme can also effectively scavenge excessive reactive oxygen species via stable multiple antioxidant enzyme activities, inhibit inflammatory cytokine secretion, and promote macrophage polarization towards M2 phenotype through MYD88/TAB/NF‐kappa B Signaling Pathway. Furthermore, CuMD‐loaded microneedle patches (CuMD‐MN) can penetrate the skin surface barrier and slowly release CuMD. In a diabetic mouse skin defect model, CuMD‐MN remarkably suppressed inflammation‐oxidative stress storm, resulting accelerated tissue regeneration wound healing. These findings highlight the potential of CuMD‐MN a promising treatment modality for diabetic wound.