作为癌症治疗的新策略之一，靶向肿瘤代谢已经引起了极大的关注。在此，我们开发了一个双重代谢抑制剂——锌肌肽金属药物纳米粒子（Zn-Car MNs）, 它表现出良好的抗铜脱除以及铜响应性药物释放，可有效抑制OXPHOS和糖酵解。值得注意的是，Zn-Car MNs可以降低细胞色素C氧化酶活性和NAD+含量，从而减少癌细胞ATP的产生，能够对肿瘤造成能源缺乏、线粒体膜电位的去极化以及增加氧化应激解导致细胞凋亡。结果表明，Zn-Car MNs在乳腺癌（对铜脱除比较敏感）和结肠癌（对铜脱除不敏感）模型中均比传统铜螯合剂tetrathiomolybdate（TM）更有效实现代谢靶向治疗。Zn-Car MNs的疗效和治疗表明了克服代谢重编程导致的药物耐药的可能性并具有潜在的临床意义。

The targeting of tumor metabolism as a novel strategy for cancer therapy has attracted tremendous attention. Herein, we develop a dual metabolism inhibitor, Zn-carnosine metallodrug network nanoparticles (Zn-Car MNs), which exhibits good Cu-depletion and Cu-responsive drug release, causing potent inhibition of both OXPHOS and glycolysis. Notably, Zn-Car MNs can decrease the activity of cytochrome c oxidase and the content of NAD+, so as to reduce ATP production in cancer cells. Thereby, energy deprivation, together with the depolarized mitochondrial membrane potential and increased oxidative stress, results in apoptosis of cancer cells. In result, Zn-Car MNs exerted more efficient metabolism-targeted therapy than the classic copper chelator, tetrathiomolybdate (TM), in both breast cancer (sensitive to copper depletion) and colon cancer (less sensitive to copper depletion) models. The efficacy and therapy of Zn-Car MNs suggest the possibility to overcome the drug resistance caused by metabolic reprogramming in tumors and has potential clinical relevance.