Cascade Nanozyme Delivering miRNA to Ischemic Heart to Alleviate Myocardial Ischemia‐Reperfusion Injury

Abstract Myocardial infarction (MI) causes cardiac dysfunction and threatens global health. Timely reperfusion following MI unavoidably contributes to additional cardiomyocyte death, a phenomenon known as myocardial ischemia/reperfusion injury (I/RI). The surge in free radicals and extensive cardiomyocyte loss significantly promote the progression toward heart failure, a condition that remains a major therapeutic challenge. Development of microRNA (miRNA)‐based therapeutics for I/RI is hindered by poor intracellular delivery of miRNA and its rapid degradation in vivo. Nanozymes with enzyme‐mimetic activities offer promising platforms for miRNA delivery while concurrently mitigating oxidative stress. Hollow ceria nanozymes decorated with gold nanoparticles (AuNPs) are developed to deliver miR‐486, whose cavernous rooms enable them to accommodate miRNA. Elevated miR‐486 expression is shown to suppress myocardial apoptosis and alleviate I/RI. Equipped with cardiac target peptide, miR‐486@CeO ₂ /Au‐pep nanoparticles are integrated with superior enzyme‐mimicking functions than a single entity, reactive oxygen species (ROS) scavenging, and improved miR‐486 delivery. In myocardial I/RI mice, miR‐486@CeO ₂ /Au‐pep can specifically accumulate at the heart and promote miR‐486 to escape from lysosomes, which further boosts the bioactivity of miR‐486 in cardiomyocytes. These combined effects confer cardioprotection and inhibit adverse ventricle remodeling. The nanosystem through synergetic works of miRNA and nanozymes provides an effective approach to treating myocardial I/RI.