Abstract / Summary
Doxorubicin (DOX) remains a potent and effective therapy for a broad spectrum of malignancies, including breast cancer, lymphomas, sarcomas, and solid tumors. However, its clinical application is limited by cumulative and often irreversible cardiotoxicity, including left ventricular dysfunction, heart failure, and arrhythmias. Mechanistically, DOX-induced cardiomyopathy involves Top2β-mediated DNA damage, mitochondrial dysfunction, excessive reactive oxygen species (ROS) generation, iron-dependent redox cycling, and impaired autophagy. Despite extensive mechanistic understanding, conventional pharmacological strategies have been largely unsuccessful in preventing cardiac injury. Therefore, strategies that preserve cardiovascular function without compromising antitumor efficacy are urgently needed. Nanoparticle-based drug delivery systems (nanocarriers) offer a promising approach by modulating pharmacokinetics and tissue biodistribution. This review highlights nanocarriers developed to mitigate DOX-induced cardiac injury. Cardioprotection primarily arises from reduced circulating free DOX, decreased myocardial accumulation, tumor-selective release, and restricted nuclear and mitochondrial exposure in cardiomyocytes. While PEGylated liposomal DOX provides clinical proof-of-concept, most next-generation nanocarriers remain preclinical. DOX-induced cardiotoxicity remains a major limitation of effective anthracycline therapy and long-term cancer survivorship. Nanocarrier-based DOX delivery can reduce myocardial exposure and cardiotoxicity while preserving antitumor efficacy. Precision control of DOX biodistribution, release, and intracellular trafficking represents a promising strategy for integrating tumor targeting with myocardial protection. Rigorous cardiovascular phenotyping and long-term clinical outcomes are essential for translating next-generation DOX nanocarriers into cardio-oncology practice.