Copper homeostasis is crucial for cells, especially for rapidly proliferating cancerous cells. Copper imbalance-induced cell death (i.e., cuproptosis) has emerged as a new strategy for tumor therapy. While copper accumulation-induced cuproptosis has been extensively investigated and its underlying mechanism recently elaborated, copper depletion-induced cuproptosis remains largely unexplored. Herein, we demonstrated copper depletion-induced tumor cuproptosis through the development of a smart copper-depleting nanodrug (i.e., ZnS nanoparticle), leveraging a cation exchange reaction between ZnS and copper ions. This cation exchange reaction is driven by the large difference in solubility product constants (Ksp) between ZnS and CuS. Our ZnS nanoparticle demonstrated a potent copper-depleting ability, which induced tumor cuproptosis both in vitro and in vivo. We proposed a copper-depleting mechanism primarily linked to the dysfunction of cellular copper-contained enzymes, contrasting with the mechanism of copper accumulation-induced cuproptosis. Furthermore, by modifying the ZnS nanoparticle with a polydopamine shell and a glucose transporter 1 DNAzyme (GD), we developed a multifunctional copper nanoconsumer with strong tumor growth and metastatic inhibition activity, enhancing copper depletion-promoted tumor therapy.

中文翻译：

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铜耗竭诱导的肿瘤 cupropsis


铜稳态对细胞至关重要，尤其是对于快速增殖的癌细胞。铜失衡诱导的细胞死亡 （即铜质沉积） 已成为肿瘤治疗的新策略。虽然铜积累诱导的铜沉积症已被广泛研究，并且最近详细阐述了其潜在机制，但铜耗竭诱导的铜沉积症在很大程度上仍未得到探索。在此，我们通过开发一种智能的耗铜纳米药物（即 ZnS 纳米颗粒），利用 ZnS 和铜离子之间的阳离子交换反应，证明了铜耗竭诱导的肿瘤钙中毒。这种阳离子交换反应是由 ZnS 和 CuS 之间溶解度产物常数 （Ksp） 的巨大差异驱动的。我们的 ZnS 纳米颗粒显示出强大的铜消耗能力，可在体外和体内诱导肿瘤 cuproposis。我们提出了一种主要与细胞含铜酶功能障碍有关的铜消耗机制，与铜积累诱导的铜消耗机制形成鲜明对比。此外，通过用聚多巴胺壳和葡萄糖转运蛋白 1 DNAzyme （GD） 修饰 ZnS 纳米颗粒，我们开发了一种具有很强肿瘤生长和转移抑制活性的多功能铜纳米消耗剂，增强了铜耗竭促进的肿瘤治疗。