Mitochondrial transfer and transplantation in cardiovascular diseases: from signaling pathways to targeted delivery strategies

Abstract Mitochondrial dysfunction drives the pathogenesis and progression of various cardiovascular diseases (CVDs). Research has demonstrated that approximately 95% of energy in the heart is supplied by mitochondrial oxidative phosphorylation (OXPHOS), and mitochondria also act as regulators of endothelial cell function, including metabolism, angiogenesis, and survival. Accordingly, mitochondrial-targeted therapies have garnered considerable research interest in CVD treatment. In contrast to traditional drug-based mitochondrial-targeted strategies, mitochondrial transfer and transplantation, as emerging innovative therapeutic approaches, hold great therapeutic promise for alleviating multiple CVDs. This article systematically reviews the molecular mechanisms and regulatory networks of endogenous/intrinsic mitochondrial transfer pathways (tunneling nanotubes, extracellular vesicles, etc.), and comprehensively summarizes the latest preclinical laboratory research, and preliminary early human clinical studies of artificial mitochondrial transplantation in major CVDs, including myocardial ischemia/reperfusion (I/R) injury, myocardial infarction (MI) and heart failure (HF). We further discuss the current critical challenges and potential risks associated with the clinical translation of this strategy, and propose targeted optimization directions and future research perspectives for its clinical application.