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Extracellular vesicles (EVs) are nanoscale extracellular vesicles derived from endocytosis that are crucial to intercellular communication. EVs possess natural biocompatibility and stability that allow them to cross biological membranes and that protect them from degradation. Recent studies have shown that EVs-mediated crosstalk between different cell types in the heart could play important roles in the maintenance of cardiac homeostasis and the pathogenesis of heart diseases. In particular, EVs secreted by different types of stem cells exhibit cardioprotective effects. However, numerous studies have shown that intravenously injected EVs are quickly cleared by macrophages of the mononuclear phagocyte system (MPS) and preferentially accumulate in MPS organs such as the liver, spleen, and lung. In this review, we discuss exosome biogenesis, the role of EVs in heart diseases, and challenges in delivering EVs …