Targeted H₂S-Mediated Gas Therapy with pH-Sensitive Release Property for Myocardial Ischemia-Reperfusion Injury by...

Management of myocardial ischemia-reperfusion injury (MIRI) in reperfusion therapy remains a major obstacle in the field of cardiovascular disease, but current available therapies have not yet been achieved in mitigating myocardial injury due to the complex pathological mechanisms of MIRI. Exogenous delivery of hydrogen sulfide (H₂S) to the injured myocardium can be an effective strategy for treating MIRI due to the multiple physiologic functions of H₂S, including anti-inflammatory, anti-apoptotic, and mitochondrial protective effects. Here, to realize the precise delivery and release of H₂S, we proposed the targeted H₂S-mediated gas therapy with pH-sensitive release property mediated by platelet membranes (PMs). In this study, a biomimetic functional poly(lactic-co-ethanolic acid) nanoparticle (RAPA/JK-1-PLGA@PM) was fabricated by loading rapamycin (RAPA; mTOR inhibitor) and JK-1 (H₂S donor) and then coated with PM. In vitro observations were conducted including pharmaceutical evaluation, H₂S release behaviors, hemolysis analysis, serum stability, cellular uptake, cytotoxicity, inhibition of myocardial apoptosis, and anti-inflammation. In vivo examinations were performed including targeting ability, restoration of cardiac function, inhibition of pathological remodeling, and anti-inflammation. RAPA/JK-1-PLGA@PM was successfully prepared with good size distribution and stability. Utilizing the natural infarct-homing ability of PM, RAPA/JK-1-PLGA@PM could be effectively targeted to the damaged myocardium. RAPA/JK-1-PLGA@PM continuously released H₂S triggered by inflammatory microenvironment, which could inhibit cardiomyocyte apoptosis, realize the transition of pro-inflammation, and alleviate myocardial injury demonstrated in hypoxia/reoxygenation myocardial cell in vitro. Precise delivery and release of H₂S attenuated inflammatory response and cardiac damage, promoted cardiac repair, and ameliorated cardiac function proven in MIRI mouse model in vivo. This research outlined the novel nanoplatform that combined immunosuppressant agents and H₂S donor with the pH-sensitive release property, offering a promising therapeutic for MIRI treatment that leveraged the synergistic effects of gas therapy.