Mitochondrial-Targeting Drug-Loaded Nanoparticles Reprogram Macrophage Metabolism via ROS/NO Co-elimination for Diabetic Wound Healing

Diabetic wounds pose a growing healthcare challenge, characterized by heavy M1 macrophage infiltration, reactive oxygen species (ROS) overproduction, tissue hypoxia, and cytokine storms. The diabetic microenvironment fails to support the critical M1-to-M2 macrophage phenotypic switch, trapping tissues in persistent pathological inflammation that disrupts natural healing processes. In this study, we developed triphenylphosphonium (TPP)-modified mitochondria-targeting nanoparticles, where liposomes encapsulated two metabolomically guided agents: aminooxyacetic acid (AOAA) to suppress nitric oxide (NO) production and hollow mesoporous manganese dioxide (H–MnO 2 ) to scavenge mitochondrial ROS and supply O 2 . In vitro, after successful mitochondrial internalization by macrophages, the nanoparticles reduced NO and ROS levels, enhanced mitochondrial respiration, and reprogrammed macrophage metabolism─shifting from aerobic glycolysis to oxidative phosphorylation (OXPHOS). This metabolic shift drove macrophage transition from pro-inflammatory M1 to anti-inflammatory M2 and thus resolved aberrant inflammation. In diabetic murine wound models, TPP-L@H–MnO 2 @AOAA further validated its efficacy. By modulating macrophage repolarization, it promoted re-epithelialization and collagen deposition. Overall, these anti-inflammatory nanoparticles with sustained-release capability provide a promising therapeutic tool for clinical management of diabetic wounds.