Engineered Extracellular Vesicle Revitalizing Macrophage Energy Metabolism for Aged Wound Repair

One major obstacle for aged wound healing is the abnormal senescence of macrophages in chronic wounds which causes immunosenescence. Tissue homeostasis depends on regulation of metabolism in accumulating senescent cells (SnCs) with aging, and cell activation for aged tissue repair requires sufficient energy. Therapeutic advancements are potential by employing metabolic strategies for intervention. First, a disorder of arginine-oxidative phosphorylation metabolism in aging skin was found, which may be the main culprit of aging. Engineered EVs (4-octyl itaconate (4OI)-EVs) which possess naturally abundance of mitochondrial proteins have been developed here. Our findings demonstrate that 4OI-engineered EV (4OI-EV) may accelerate the repair of aged mouse skin and diabetic mouse skin, reduce cellular senescence, and recover cell dysfunctions. After 4OI-EV therapy, metabolism has been notably altered, with decreased glycolysis and increased arginine-oxidative phosphorylation axis through enhanced argininosuccinate synthetase 1 (ASS1) level. We demonstrate how 4OI-EV partially restores macrophages senescence by reversing mitochondrial dysfunctions and mitophagy suppressions via ASS1 which may be identified as a potential effective target for alleviating skin aging.