Mesenchymal Stromal Cell-Derived Extracellular Vesicles Mediate Mitochondrial Delivery in Injury: Mechanistic Insights, Evidentiary Tiers, and Translational Challenges.

While mesenchymal stromal cell (MSC)-derived extracellular vesicles (MSC-EVs) offer a safer, cell-free alternative to stem cell transplantation, their specific role in rescuing recipient cell mitochondrial networks requires precise definition. This review clarifies that scientific landscape by systematically partitioning MSC-EV-mediated mitochondrial delivery into three rigorous, evidence-based categories: (i) the horizontal transfer of intact, bioenergetically active mitochondria, (ii) the lateral delivery of sub-organellar components such as mitochondrial DNA (mtDNA) and transcriptional proteins (e.g., TFAM), and (iii) indirect protective signaling that rejuvenates endogenous networks. Effectively integrated cargo within MSC-EV has been reported to restore mitochondrial membrane potential, contributing to the stabilization of electron transport chain complexes (I-IV), the reactive oxygen species (ROS) balance, and the tricarboxylic acid (TCA) cycle and NAD + /NADH balance to reverse bioenergetic collapse. Across diverse myocardial, pulmonary, hepatic, renal, and neurological injury models, this EV-associated delivery is associated with dampening of hyper-inflammation, enhances macrophage phagocytosis, and supports tissue barrier regeneration. Nevertheless, critical translational barriers remain, including significant EV heterogeneity, a lack of standardized high-purity isolation protocols in line with MISEV (Minimal Information for Studies of Extracellular Vesicles) guidelines, and unverified oncologic risks such as supporting tumor progression or chemoresistance through unintended metabolic rescue. In conclusion, large-scale clinical adoption requires prioritized, well-designed human trials with rigorous cargo characterization to firmly establish long-term safety, durability, and oncologic security.