Myocardial ischemia/reperfusion injury (MI/RI) remains a major challenge in the treatment of acute myocardial infarction due to the lack of effective therapeutic options. Despite advancements in interventional techniques like percutaneous coronary intervention, MI/RI-induced oxidative stress, inflammatory responses, and cardiomyocyte apoptosis still lead to poor long-term prognosis for patients. While mesenchymal stromal cells (MSCs) and their derivates show promising potential for MI/RI therapy, their clinical application is hindered by low transplantation efficiency—often resulting from poor cell retention in the ischemic myocardium—and insufficient yield for large-scale clinical use. In this study, we engineered nanoscale artificial cell-derived vesicles (ACDVs) by extruding Ginsenoside Rg1-primed MSCs (Rg1-MSCs), resulting in Rg1-ACDVs. Rg1-ACDVs displayed superior therapeutic efficacy compared to non-primed ACDVs and extracellular vesicles derived from Rg1-MSCs (Rg1-EVs), as evidenced by reduced myocardial infarct size in rat MI/RI models. Multi-omics analysis revealed that Rg1-ACDVs possess distinct molecular signatures associated with promoting cell cycle progression and reducing DNA damage, including upregulated expression of DNA repair-related proteins and cell cycle regulators. These findings were further validated experimentally, demonstrating that Rg1-ACDVs effectively reduce reactive oxygen species (ROS) accumulation—an important driver of MI/RI—and mitigate DNA damage both in vitro (in cultured cardiomyocytes) and in vivo (in rat MI/RI models). This study highlights the synergistic benefits of combining Ginsenoside Rg1 priming (which modulates MSC paracrine function) with nanoscale engineering (which optimizes vesicle delivery), and introduces Rg1-ACDVs as a scalable and innovative strategy, offering a promising approach for improving clinical outcomes in MI/RI therapy.