CeVO4-Ti nanozymes-laden dendrobium officinale-derived nanovesicles combined with hydrogel to promote diabetic wound healing by modulating mitochondrial function

• Ti doping enhances the catalytic enzyme activity of CTT, effectively scavenging ROS. • DOEVs as a synergistic therapy and drug delivery platform for wound healing. • DOEVs@CTT/DHM activates Nrf2/Parkin/Pink1 pathway to restore mitochondrial function. • DOEVs@CTT/DHM reduces oxidative stress and enhances angiogenesis for wound healing. Refractory diabetic wound is characterized by excessive oxidative stress and inadequate angiogenesis, both of which are primarily caused by mitochondrial dysfunction. Although nanozymes exhibit multiple enzyme-mimicking antioxidant activities, challenges such as immune rejection, limited catalytic activity, and poor biocompatibility remain. Here in, a novel therapeutic system based on plant exosome nanovesicle-incorporated nanozymes was designed to mitigate oxidative stress and promote healing in diabetic wounds by targeting and restoring mitochondrial function. Titanium-doped cerium vanadate (CeVO 4 -Ti) nanozymes with multiple enzyme catalytic activities had been rationally designed. The surface of CeVO 4 -Ti was modified with triphenylphosphine (TPP) to endow mitochondrial targeting. To enhance biosafety and delivery, the nanozymes were further encapsulated within dendrobium officinale-derived nanovesicles (DOEVs) and integrated into a dopamine-methacrylated hyaluronic acid (DHM) hydrogel, forming a composite system (DOEVs@CTT/DHM). DOEVs@CTT/DHM could effectively mimic the activity of natural enzymes, eliminate reactive oxygen species, reconstruct blood vessels, and promote re-epithelialization, thereby facilitating wound healing from multiple perspectives. Crucially, it activated the Nrf2/Parkin/Pink1 pathway to regulate mitophagy, thereby revitalizing mitochondrial function and then alleviating oxidative stress. This study presents a novel strategy for mitochondrial regulation, advancing the development of multifunctional nanozyme-based biomaterials for wound healing.