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Abstract Ischemia-reperfusion injury (IRI) poses significant challenges across various organ systems, including the heart, brain, and kidneys. Exosomes have shown great potentials and applications in mitigating IRI-induced cell and tissue damage through modulating inflammatory responses, enhancing angiogenesis, and promoting tissue repair. Despite these advances, a more systematic understanding of exosomes from different sources and their biotransport is critical for optimizing therapeutic efficacy and accelerating the clinical adoption of exosomes for IRI therapies. Therefore, this review article overviews the administration routes of exosomes from different sources, such as mesenchymal stem cells and other somatic cells, in the context of IRI treatment. Furthermore, this article covers how the delivered exosomes modulate molecular pathways of recipient cells, aiding in the prevention of cell death and the promotions of regeneration in IRI models. In the end, this article discusses the ongoing research efforts and propose future research directions of exosome-based therapies. Graphical Abstract