Repurposing Sildenafil Using Reactive Oxygen Species-Responsive Silica-Cross-Linked Nanomicelles for the Attenuation of Myocardial Ischemia−Reperfusion Injury

Abstract Reperfusion therapy is the standard treatment for acute myocardial infarction, yet it paradoxically induces myocardial ischemia−reperfusion injury (MI/RI), resulting in further cardiomyocyte loss. Effective therapies for MI/RI therefore remain a major unmet clinical need. Sildenafil, a clinically approved phosphodiesterase type 5 (PDE5) inhibitor used for erectile dysfunction and pulmonary arterial hypertension, has shown potential cardioprotective activity through the enhancement of nitric oxide−cyclic guanosine monophosphate (NO−cGMP) signaling and vasodilation. However, its therapeutic utility in MI/RI is limited by nonspecific biodistribution and insufficient accumulation at the site of injury. Here, we developed a reactive oxygen species-responsive, silica-cross-linked micellar nanoplatform for systemic sildenafil delivery. This nanoplatform promotes preferential accumulation in the infarcted myocardium and enables ROS-triggered drug release within the pathological microenvironment. In a rat model of MI/RI, intravenous administration of the nanomedicine significantly improved cardiac function, reduced apoptosis and fibrosis, and markedly alleviated myocardial injury. These findings highlight a promising therapeutic strategy for MI/RI and support the expanded clinical application of sildenafil.