Metformin Syncs CeO2 to Recover Intra‐ and Extra‐Cellular ROS Homeostasis in Diabetic Wound Healing

Abstract Excessive generation of reactive oxygen species (ROS) poses a huge obstacle to the healing process of diabetic wounds, resulting in chronic, non‐healing wounds. While numerous anti‐ROS therapeutics have been developed, satisfied intra‐ and extra‐ cellular ROS homeostasis is hard to be established in diabetic wounds. To address this issue, a nanoparticle via loading metformin and CeO 2 into mesoporous silica (MSN@Met‐CeO 2 ) is designed and synthesized, which is then encapsulated within ROS‐responsive hydrogel and shaped as microneedles (MNs) for better application in diabetic wounds. Interestingly, a unique metformin‐cerium chelate (Ce· 3Metformin) is formed during the synthesis of MSN@Met‐CeO 2 MN, which significantly strengthened the inhibitory effect of metformin on mitochondrial complex I. With the presence of Ce· 3Metformin, MSN@Met‐CeO 2 MN performed a remarkable effect on intracellular mtROS reduction as well as extracellular ROS elimination, the latter is primarily accomplished through the dissociative CeO 2 in MSN@Met‐CeO 2 MN. In the mouse diabetic wound model, MSN@Met‐CeO 2 MN exhibited a superior pro‐healing effect with accelerated inflammation resolution and enhanced angiogenesis, thus highlighting its significant potential for clinical application