Mitochondrial Transplantation: An Emerging Therapeutic Option for Cardiovascular Disease.

Cardiovascular diseases (CVD) continue to impose the greatest global burden of death, and mitochondrial injury is increasingly recognized as a key pathological driver across ischemic heart disease, cardiac arrest, and heart failure. In this context, mitochondrial transplantation (MT) has gained attention as a promising therapeutic approach that directly addresses bioenergetic deficits by delivering functional mitochondria to compromised myocardium. This review examines current evidence for MT in CVD and evaluates its translational potential. We comprehensively reviewed preclinical studies and early clinical data on MT in CVD models, focusing on isolation techniques, delivery mechanisms, cellular uptake pathways, and therapeutic outcomes. Key databases were searched for relevant studies published through November 2025. MT demonstrates significant cardioprotective effects across diverse CVD models, including reduction in infarct size, restoration of adenosine triphosphate production, and improved functional recovery. Multiple cellular uptake mechanisms have been investigated, including actin-dependent endocytosis, macropinocytosis, and tunneling nanotubes. Advanced delivery strategies incorporating surface modifications, hydrogel platforms, and targeted peptides have improved mitochondrial stability and homing efficiency. Proposed mechanisms extend beyond bioenergetic rescue to include modulation of autophagy, oxidative stress reduction, and immunometabolic regulation. However, critical challenges remain regarding uptake efficiency, biodistribution, persistence, standardization protocols, and immunological considerations. MT represents a paradigm-shifting approach to cardiovascular therapeutics with encouraging preclinical results. Rigorous clinical trials with standardized methodologies are essential to establish safety, efficacy, and optimal implementation strategies for clinical translation.