Depletion of mitochondrial copper, which shifts metabolism from respiration to glycolysis and reduces energy production, is known to be effective against cancer types that depend on oxidative phosphorylation. However, existing copper chelators are too toxic or ineffective for cancer treatment. Here we develop a safe, mitochondria-targeted, copper-depleting nanoparticle (CDN) and test it against triple-negative breast cancer (TNBC). We show that CDNs decrease oxygen consumption and oxidative phosphorylation, cause a metabolic switch to glycolysis and reduce ATP production in TNBC cells. This energy deficiency, together with compromised mitochondrial membrane potential and elevated oxidative stress, results in apoptosis. CDNs should be less toxic than existing copper chelators because they favorably deprive copper in the mitochondria in cancer cells instead of systemic depletion. Indeed, we demonstrate low toxicity of CDNs in healthy mice. In three mouse models of TNBC, CDN administration inhibits tumor growth and substantially improves survival. The efficacy and safety of CDNs suggest the potential clinical relevance of this approach.

众所周知，线粒体铜的消耗可将代谢从呼吸转变为糖酵解并减少能量产生，可有效对抗依赖氧化磷酸化的癌症类型。然而，现有的铜螯合剂对于癌症治疗来说毒性太大或无效。在这里，我们开发了一种安全的、靶向线粒体的铜消耗纳米颗粒 (CDN)，并测试它对三阴性乳腺癌 (TNBC) 的抵抗力。我们发现 CDN 可以减少 TNBC 细胞中的耗氧量和氧化磷酸化，导致代谢转变为糖酵解，并减少 ATP 的产生。这种能量缺乏，加上线粒体膜电位受损和氧化应激升高，导致细胞凋亡。CDN 的毒性应该比现有的铜螯合剂低，因为它们有利于剥夺癌细胞线粒体中的铜，而不是全身耗竭。事实上，我们在健康小鼠中证明了 CDN 的低毒性。在三种 TNBC 小鼠模型中，CDN 给药可抑制肿瘤生长并显着提高生存率。CDN 的有效性和安全性表明了这种方法的潜在临床意义。