A Bioengineered Mitochondrial Respiration‐Mimetic Copper‐Based Metal‐Organic Framework Reprogramming Oxidative Phosphorylation to Enhance Tumor Cuproptosis

Mitochondrial metabolism-dependent cuproptosis has emerged as a promising anticancer modality, yet its efficacy is constrained by the hypoxic and glycolysis-dominant tumor microenvironment that suppresses oxidative phosphorylation (OXPHOS). Strategies that simultaneously overcome hypoxia and mitochondrial metabolic resistance remain underexplored. Herein, we report a bioengineered mitochondrial respiration-mimetic nanoplatform (TC@OMG) that renews tumor mitochondrial metabolism to enhance cuproptosis. TC@OMG integrates a copper-based metal-organic framework co-loaded with glucose oxidase and a lactate dehydrogenase inhibitor, and is cloaked with a hybrid membrane derived from tumor cells and plant thylakoids, enabling tumor targeting and photosynthetic oxygen generation. Mechanistically, photo-triggered TC@OMG couples hypoxia alleviation with glycolysis inhibition to enforce a metabolic shift toward mitochondrial OXPHOS, thereby sensitizing tumor cells to cuproptosis. Concurrently, its microenvironment-responsive copper release and glutathione depletion disrupt mitochondrial Fe-S cluster homeostasis and induce aggregation of lipoylated proteins, ultimately promoting cuproptotic cell death. In vivo, photo-triggered TC@OMG achieves efficient tumor targeting, hypoxia relieving, and tumor inhibiting effects across multiple melanoma models, including subcutaneous, metastatic, and intraocular tumors. Collectively, this work bioengineered a respiration-mimetic nanotherapeutic strategy that integrates mitochondrial metabolic reprogramming with copper-dependent cell death, providing a generalizable strategy for overcoming mitochondrial metabolic resistance in cancer therapy.