Abstract

Myocardial ischemia-reperfusion injury (MIRI) is a key obstacle that restricts the efficacy of reperfusion therapy after myocardial infarction (MI). Ferroptosis hold a central role in the pathological process of MIRI. Emerging evidence suggests that Fe 2+ released by mitoNEET in the mitochondrial membrane is a key factor in the simultaneous exacerbation of mitochondrial damage and ferroptosis under stress. However, traditional ferroptosis inhibitors lack the ability to target subcellular organelles, making it difficult to precisely intervene in this process. To address this challenge, this study pioneered a dual Fe 2+ -clean (DFC) nanotherapeutic system to stabilize mitoNEET and effectively alleviate MIRI. DFC is constructed based on melanin hollow nanomaterials with a single large pore, and hold both myocardial infarction targeting and mitochondrial targeting capabilities. In the acidic microenvironment of the infarct area, DFC can controllably release miglitazone (MGZ), a highly effective stabilizer of mitoNEET. This work achieved the first precise regulation of mitoNEET function at the subcellular organelle level, enhancing the stability of mitoNEET's [2Fe-2S] cluster, blocking Fe 2+ leakage at the source, and thereby simultaneously reducing the Fe 2+ load in mitochondria and cytoplasm. At ultra-low doses, DFC can significantly inhibit cardiomyocyte ferroptosis, improve mitochondrial function and alleviate MIRI. This research develops breakthrough strategies for ferroptosis-related diseases.