Cu Nanowires Trigger Efficient Cuproptosis via Special Intracellular Distribution and Excessive Cu Ion Release.

Cuproptosis, dependent on Cu overload, presents novel opportunities for cancer therapy. Cu-based nanomaterials have shown excellent advantages for the intracellular delivery of Cu. However, the biological process of Cu nanomaterials transporting Cu ions into cancer cells remains unclear. In this study, we tracked the Cu ion release process of copper nanowires (CuNWs) and copper nanoparticles (CuNPs) at the single-cell level. CuNWs with 5-μm length and CuNPs were found to be completely internalized by cancer cells. Interestingly, CuNWs escaped from the endolysosomal system, whereas CuNPs were mainly trapped in the lysosomes. This specific intracellular distribution of CuNWs led to cytoplasmic Cu ion overload, directly damaging mitochondria and inducing dihydrolipoamide S-acetyltransferase (DLAT) protein aggregation. Through these excessive Cu ions, CuNWs triggered more efficient cuproptosis than CuNPs to further increase cell death. Thus, CuNWs are more effective in delivering Cu ions than CuNPs, providing a novel perspective for designing cuproptosis-based functional nanomaterials for cancer therapy.