Mitochondria‐Targeted Ferroptosis Nanodrug for Triple‐Negative Breast Cancer Therapy via Fatty Acid Metabolism Remodeling and Tumor Bacterial Symbiosis Inhibition

Abstract Triple‐negative breast cancer (TNBC) is considered one of the most aggressive subtypes of breast cancer, due to its pronounced propensity for metastasis. This challenge is amplified by the critical role of mitochondria in metastasis, regulating processes like fatty acid metabolism that drive tumor cell migration. Moreover, emerging evidence suggests that bacterial infiltration, particularly Staphylococcus xylosus ( S. xylosus ), could further exacerbate TNBC metastasis. To address both metabolic dysregulation and bacterial involvement, a mitochondria‐targeted ferroptosis‐activated nanosystem is developed, named ICM, which is integrated the mitochondrial membrane (MM) for mitochondrial targeting, the FeCl 3 for ferroptosis therapy, the photosensitizer indocyanine green, and cytochrome c (CytC) through self‐assembly technology. During assembly, CytC interacted with cardiolipin on the MM, endowing ICM with peroxidase‐like and catalase‐like activities. Dual enzymatic activities, combined with phototherapy, enhance FeCl 3 ‐induced ferroptosis in tumor cell mitochondria, thereby reprogramming fatty acid metabolism and inhibiting metastasis. Additionally, the amplified ferroptosis effects also effectively inhibit S. xylosus , disrupting the tumor‐bacteria symbiosis and further preventing metastatic spread. Finally, ICM nanoparticles significantly suppress TNBC metastasis by modulating lipid metabolism and inhibiting bacterial‐mediated metastasis. These findings suggest that ICM offer a multifaceted therapeutic approach for combating TNBC metastasis, providing a potential strategy for cancer treatments.