Copper depletion-induced tumor cuproptosis

Copper homeostasis is crucial for cells, especially for rapidly proliferating cancerous cells. Copper imbalance-induced cell death (<i>i.e.</i>, 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>i.e.</i>, ZnS nanoparticles), leveraging a cation exchange reaction between ZnS and copper ions. This cation exchange reaction is driven by the large difference in solubility product constants (<i>K</i> _sp) between ZnS and CuS. Our ZnS nanoparticles demonstrated a potent copper-depleting ability, which induced tumor cuproptosis both <i>in vitro</i> and <i>in vivo</i>. 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.