In Vivo Reprogramming of Tissue‐Derived Extracellular Vesicles for Treating Chronic Tissue Injury Through Metabolic Engineering

Abstract Extracellular vesicles (EVs) have emerged as promising therapeutics for regenerative medicine, but the efficacy of current exogenous EV‐based therapies for treating chronic tissue injury is still unsatisfactory. Exercise can affect skeletal muscle EV secretion and that this process regulates the systemic health‐promoting role of exercise, suggesting that fine‐tuning of endogenous tissue EV secretion may provide a new therapeutic avenue. Here, this work reports that in vivo reprogramming of EV secretion via metabolic engineering is a promising strategy for treating chronic diseases. Briefly, exercise enhanced mitochondrial metabolism and EV production in healthy skeletal muscles, and EVs from healthy skeletal muscles subjected to exercise or metabolic engineering (boosting mitochondrial biogenesis via AAV‐mediated muscle‐specific TFAM overexpression) exerted cellular protective effects in vitro. In injured skeletal muscles, in vivo metabolic engineering therapy could reprogram EV secretion patterns (reducing pathological EV compositions while increasing beneficial EV compositions) by regulating multiple EV biogenesis and cargo sorting pathways. Reprogrammed muscle‐derived EVs could reach major organs and tissues via the circulation and then simultaneously attenuated multiple‐tissue (e.g., muscle and kidney) injury in chronic kidney disease. This study highlights that in vivo reprogramming of tissue‐derived EVs via a metabolic engineering approach is a potential strategy for treating diverse chronic diseases.