Stem Cell-Derived Extracellular Vesicle Therapy in Ischemic Brain Injuries.

Ischemic brain injury (IBI), including stroke and cardiac arrest-induced global cerebral injury, presents a significant clinical challenge due to its high morbidity and incidence of neurological deficits. Currently, effective strategies for neurological repair remain limited. Extracellular vesicles (EVs) are a diverse group of cell-derived, lipid-bound nanoparticles that encapsulate RNAs, proteins, lipids, metabolites, growth factors, and cytokines. EVs play an essential role in intercellular communication and are involved in various physiological and pathological processes. Stem cell-derived EVs (SC-EVs) have been studied in the context of IBI, demonstrating regenerative and angiogenic effects that resemble those of their parent stem cells, holding promise for improved cell-free treatment of IBI. This review provides comprehensive insights into the therapeutic application of SC-EVs in IBI, including an SC-EV source comparison with their distinct advantages and limitations, and dissects the multifaceted mechanisms of SC-EVs including immunomodulation, neurogenesis, mitochondrial transfer, and myelin repair. Furthermore, it highlights recent advances in engineering SC-EV cargo and surfaces for enhanced targeting and efficacy in IBI treatment. It also emphasizes strategies to improve the reproducibility of in vivo studies through standardized protocols and bridges the gap between preclinical findings and early clinical trials. Finally, the review critically addresses ethical challenges and equity considerations, providing a roadmap for the responsible translation of SC-EV therapies into clinical practice.