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 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.