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

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@CeO2/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@CeO2/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.