Mitochondrial Metabolism Targeted Nanoplatform for Efficient Triple‐Negative Breast Cancer Combination Therapy

Abstract Tumor reprogram pathway of mitochondrial metabolism is an emerging approach for malignant tumor treatment, such as triple‐negative breast cancer. In this study, a tumor/mitochondria cascaded targeting, adenosine‐triphosphate (ATP) responsive nanocarrier of zeolitic imidazolate framework‐90 (ZIF‐90) for breast cancer combination therapy is reported. Atovaquone (AVO) and hemin are loaded into ZIF‐90, then a peptide iRGD with tumor‐targeting ability is modified on the ZIF‐90 nanoplatform. Hemin can specifically degrade BTB and CNC homology1 (BACH1), resulting in the changes of mitochondrial metabolism, and AVO acts as the inhibitor of the electron transport chain (ETC). The degradation of BACH1 using hemin can effectively improve the anti‐tumor efficiency of mitochondrial metabolism inhibitor AVO, by increasing dependency on mitochondrial respiration. This nanoplatform displays both tumor‐targeting and mitochondria‐targeting capacity with high level of ATP responsive drug release behavior. The specific characteristic of mitochondria‐targeting ability of this nanoplatform can increase the accumulation of AVO in the mitochondria, and in turn, can effectively improve the inhibition of the ETC. Both in vitro and in vivo results reveal that this composite nanocarrier has excellent tumor inhibition ability with limited side effects. Accordingly, this study provides an attractive strategy in the mitochondrial metabolism for cancer targeted therapy.