Macrophage‐Targeted Efferocytosis Therapy Promotes Diabetic Wound Healing via Cellular Level Debridement

Abstract Impaired efferocytosis in diabetic wounds contributes to apoptotic cell accumulation, chronic inflammation, and poor healing outcomes. In this study, a multi‐hierarchical hydrogel designed to facilitate cellular debridement and initiate a healing process in diabetic wounds is proposed. A reactive oxygen species (ROS)/glucose‐responsive hydrogel conjugated with chemokine aptamers is developed that encapsulated mannose‐modified lipid nanoparticles (mLNPs) loaded with ADAM17 siRNA (A disintegrin and metalloproteinase 17). This hydrogel enhanced macrophage recruitment by enriching endogenous chemokines. Additionally, it responded to the pathological microenvironment, enabling the dynamic release of mLNPs for targeted siRNA delivery to macrophages. Treatment with ADAM17 siR@mLNPs significantly enhanced macrophage efferocytosis through the MerTK‐Rac1 pathway and glycolytic reprogramming, thereby initiating the resolution of inflammation and tissue repair. Finally, in animal models of diabetic wounds, this therapy reduced the apoptotic burden and improved wound healing. In conclusion, macrophage‐targeted efferocytosis‐reactivation therapy is a promising strategy for the treatment of diabetic wounds.