The management of myocardial ischemia/reperfusion (I/R) damage in the context of reperfusion treatment remains a significant hurdle in the field of cardiovascular disorders. The injured lesions exhibit distinctive features, including abnormal accumulation of necrotic cells and subsequent inflammatory response, which further exacerbates the impairment of cardiac function. Here, we report genetically engineered hybrid nanovesicles (hNVs), which contain cell-derived nanovesicles overexpressing high-affinity SIRPα variants (SαV-NVs), exosomes (EXOs) derived from human mesenchymal stem cells (MSCs), and platelet-derived nanovesicles (PLT-NVs), to facilitate the necrotic cell clearance and inhibit the inflammatory responses. Mechanistically, the presence of SαV-NVs suppresses the CD47-SIRPα interaction, leading to the promotion of the macrophage phagocytosis of dead cells, while the component of EXOs aids in alleviating inflammatory responses. Moreover, the PLT-NVs endow hNVs with the capacity to evade immune surveillance and selectively target the infarcted area. In I/R mouse models, coadministration of SαV-NVs and EXOs showed a notable synergistic effect, leading to a significant enhancement in the left ventricular ejection fraction (LVEF) on day 21. These findings highlight that the hNVs possess the ability to alleviate myocardial inflammation, minimize infarct size, and improve cardiac function in I/R models, offering a simple, safe, and robust strategy in boosting cardiac repair after I/R.