Nanoparticle-enabled strategies to reduce doxorubicin-induced cardiotoxicity

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.