Delivery of mitochondria-containing extracellular vesicles to the BBB for ischemic stroke therapy

INTRODUCTION: ), contain functional mitochondrial components. Therefore, development of BEC-derived mitochondria-containing EVs for delivery to the BBB will (1) alleviate mitochondrial dysfunction and limit long-term neurological dysfunction in ischemic stroke and (2) provide an alternative therapeutic option for treating numerous other diseases associated with mitochondrial dysfunction. AREA COVERED: This review will discuss (1) how EV subsets package different types of mitochondrial components during their biogenesis, (2) mechanisms of EV internalization and functional mitochondrial responses in the recipient cells, and (3) EV biodistribution and pharmacokinetics - key factors involved in the development of mitochondria-containing EVs as a novel BBB-targeted stroke therapy. EXPERT OPINION: Mitochondria-containing MVs have demonstrated therapeutic benefits in ischemic stroke and other pathologies associated with mitochondrial dysfunction. Delivery of MV mitochondria to the BBB is expected to protect the BBB integrity and neurovascular unit post-stroke. MV mitochondria quality control, characterization, mechanistic understanding of its effects in vivo, safety and efficacy in different preclinical models, large-scale production, and establishment of regulatory guidelines are foreseeable milestones to harness the clinical potential of MV mitochondria delivery.