Milk-derived exosomes carrying siRNA-KEAP1 promote diabetic wound healing by improving oxidative stress

Abstract Diabetic wound, as a serious complication of diabetes mellitus (DM), leads to persistent infection, amputation and even death. Prolonged oxidative stress has been widely recognized as the main cause of diabetic wound and is considered as hopeful therapeutic target. In the present study, Keap1/Nrf2 signaling was confirmed to be activated in streptozotocin (STZ)-induced diabetic mice and methylglyoxal (MGO)-treated human umbilical vein endothelial cells (HUVEC). Knockdown of Keap1 by siRNA attenuated the raised Keap1 level, promoted the nuclear transfer of Nrf2, and then facilitated the expression of HO-1, an antioxidant protein. Then the milk-derived exosomes (mEXOs) were developed as a novel, efficient and non-toxic siRNA carrier. SiRNA-Keap1 (siKeap1) was loaded into mEXOs through ultrasonic technique, which promoted HUVEC proliferation, migration and relieved oxidative stress in MGO-treated HUVEC. In the meantime, the injection of mEXOs-siKeap1 significantly accelerated the diabetic wound healing with enhanced collagen formation and neovascularization in mice models. Totally, the present study puts forward a potential treatment for diabetic wound and proved the feasibility of mEXOs as a scalable, biocompatible, and cost-effective siRNA delivery system.