BACKGROUND: NOD-like receptor thermal protein domain associated protein 3 (NLRP3)-mediated pyroptosis of cardiomyocytes is a key contributor to the progression of myocardial infarction (MI). This study aimed to investigate whether exosomes derived from human induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSC-EXOs) could protect against MI by inhibiting cardiomyocyte pyroptosis and explore the underlying mechanisms. METHODS: Exosomes from human bone marrow-MSCs (BM-MSC-EXOs) and iPSC-MSCs (iPSC-MSC-EXOs) were collected and intramuscularly injected into the peri-infarct region of a mouse MI model. Cardiac function was assessed four weeks post-injection. Myocardial pyroptosis was evaluated using TUNEL staining and measurement of associated factors. Neonatal mouse cardiomyocytes (NMCMs) exposed to serum deprivation and hypoxia (SD/H) were treated with BM-MSC-EXOs or iPSC-MSC-EXOs. A loss-of-function approach was employed to examine the role of iPSC-MSC-exosomal-miR-202-5p in regulating cardiomyocyte pyroptosis. RESULTS: Compared to BM-MSC-EXOs, iPSC-MSC-EXOs demonstrated superior improvement in cardiac function in MI mice. Both BM-MSC-EXOs and iPSC-MSC-EXOs reduced cardiomyocyte pyroptosis by downregulating proteins NLRP3, ASC, Caspase-1, and gasdermin D-NT, as well as inflammatory factors in MI mice and SD/H-treated NMCMs. iPSC-MSC-EXOs exhibited greater protective effects. MicroRNA sequencing revealed higher levels of miR-202-5p in iPSC-MSC-EXOs than in BM-MSC-EXOs. The protective effect of iPSC-MSC-EXOs against cardiomyocyte pyroptosis was partially reversed by miR-202-5p knockdown. Mechanistically, miR-202-5p in iPSC-MSC-EXOs inhibited cardiomyocyte pyroptosis by downregulating the TRAF3IP2/JNK pathway. CONCLUSIONS: iPSC-MSC-EXOs protect against MI by inhibiting cardiomyocyte pyroptosis via miR-202-5p-mediated suppression of the TRAF3IP2/JNK axis. These findings suggest a promising therapeutic approach for MI.