Copper depletion-induced tumor cuproptosis

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 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 (K _sp) between ZnS and CuS. Our ZnS nanoparticles 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.