Superoxide Dismutase‐Loaded Nanoparticles Attenuate Myocardial Ischemia‐Reperfusion Injury and Protect against Chronic Adverse Ventricular Remodeling

Early revascularization is critical to reduce morbidity after myocardial infarction, although reperfusion incites additional oxidative injury. Superoxide dismutase (SOD) is an antioxidant that scavenges reactive oxygen species (ROS) but has low endogenous expression and rapid myocardial washout when administered exogenously. This study utilizes a novel nanoparticle carrier to improve exogeneous SOD retention while preserving enzyme function. Its role is assessed in preserving cardiac function after myocardial ischemia‐reperfusion (I/R) injury. Here, nanoparticle‐encapsulated SOD (NP‐SOD) exhibits similar enzyme activity as free SOD, measured by ferricytochrome‐c assay. In an in vitro I/R model, free and NP‐SOD reduce active ROS, preserve mitochondrial integrity, and improve cell viability compared to controls. In a rat in vivo I/R injury model, NP‐encapsulation of fluorescent‐tagged SOD improves intramyocardial retention after direct injection. Intramyocardial NP‐SOD administration in vivo improves left ventricular contractility at 3‐h post‐reperfusion by echocardiography and 4‐weeks by echocardiography and invasive pressure–volume catheter analysis. These findings suggest that NP‐SOD mitigates ROS damage in cardiac I/R injury in vitro and maximizes retention in vivo. NP‐SOD further attenuates acute injury and protects against myocyte loss and chronic adverse ventricular remodeling, demonstrating potential for translating NP‐SOD as a therapy to mitigate myocardial I/R injury. Encapsulating superoxide dismutase, a potent but transitory antioxidant, within a semipermeable nanoparticle construct protects from proteolytic cleavage while maintaining its antioxidant activity. In an in vivo model of myocardial ischemia/reperfusion injury, direct intramyocardial administration of this antioxidant‐nanoparticle construct protects myocardium against damage from reactive oxygen species. This preserves ventricular structure and function in both acute and chronic settings.