Exosome-Mitochondrial Hybrid Membrane with Targeted Delivery of CO Prevents Mitochondrial Dysfunction and Pyroptosis against Myocardial Ischemia-Reperfusion Injury

Myocardial ischemia-reperfusion (I/R) injury exacerbates cardiac dysfunction and heart failure following clinical revascularization. The main mechanisms involve aberrant accumulation of reactive oxygen species (ROS) that induce mitochondrial dysfunction, trigger pyroptosis, and amplify immune-inflammatory responses. Herein, we developed exosome-mitochondrial hybrid membrane vessels to encapsulate carbon monoxide (EM@CO) for targeted delivery of CO to attenuate myocardial I/R injury. Due to the adhesive properties of exosomes and the homologous mitochondrial targeting capacity of the mitochondrial membrane (MM), EM@CO exhibits sequential targeting from infarcted myocardium to myocardial cell mitochondria. The released CO in mitochondria reduces abnormal mitochondrial ROS generation to maintain mitochondrial function, thereby decreasing mtDNA release and inhibiting pyroptosis in vitro and in vivo. Moreover, a single intravenous injection of EM@CO attenuates inflammatory amplification in cardiac tissue by promoting M1 to M2 macrophage polarization. It can effectively decrease the pro-inflammatory cytokine release and inhibit inflammation, thereby attenuating myocardial infarction and improving cardiac function. In summary, the findings of this study reveal the potential for restoring mitochondrial function through targeted gas therapy to eliminate reactive oxygen species (ROS) and inhibit cellular pyroptosis, which holds promise for ameliorating myocardial ischemia-reperfusion injury.