Ultrasound-Triggered piRNA Delivery Using Biomimetic Phase-Changeable Nanoparticles for Theranostics of Myocardial Infarction.

Myocardial infarction (MI) remains a major cause of cardiovascular morbidity, and effective strategies to prevent adverse remodeling are limited. Here, we identify piR-1873 as a cardioprotective piRNA that is down-regulated in MI patients, mouse models, and H2O2-treated cardiomyocytes. Serum piR-1873 levels correlated with MI biomarkers, suggesting its potential as a complementary biomarker, with an area under the curve (AUC) of 0.8389. Mechanistically, piR-1873 directly targeted Usp2 and inhibited RIP1/RIP3/MLKL-mediated necroptosis. To achieve efficient delivery, we developed ultrasound (US)-responsive piRNA nanoparticles (piR-NPs) consisting of a perfluorohexane (PFH) phase-change core loaded with piR-1873 and coated with a cardiomyocyte membrane shell. In vitro, piR-NPs enhanced piR-1873 delivery and suppressed cardiomyocyte necroptosis, with US further improving these effects. In MI mice, piR-NPs accumulated in infarcted myocardium, and US enhanced nanoparticle retention, resulting in improved cardiac function, reduced fibrosis, and attenuated necroptosis without detectable systemic toxicity. Collectively, this study reveals the diagnostic and therapeutic potential of piR-1873 and establishes a biomimetic, US-triggered piRNA delivery platform for MI treatment.