Orchestrated Photothermal Nanoreactor Promoted Cuproptosis for Synergistic Cancer Therapy Through Glutathione Depletion and Gene Regulation

ABSTRACT Cuproptosis, a novel form of copper‐dependent cell death, holds great promise for cancer therapy. However, the induction of cuproptosis is challenged by its reliance on copper ions and the high levels of glutathione (GSH) in the tumor microenvironment. In this study, an all‐in‐one nanoparticle, ICG‐Cu‐ASO was developed for triple‐negative breast cancer (TNBC) treatment, integrating dual phototherapy with a copper‐mediated metabolic disruption strategy via a cascading mechanism. Under NIR irradiation, indocyanine green (ICG) enhances cuproptosis through generating reactive oxygen species to deplete GSH, while antisense oligonucleotides (ASO) targeting HSP90 silence heat stress protection to amplify mild photothermal effects. In addition, excess Cu 2+ also reacts with GSH, reducing its inhibitory effect on cuproptosis. The pH‐responsive nanoparticle releases components in the tumor niche and features excellent photothermal conversion efficiency for spatiotemporal dual therapy control. Leveraging TNBC cells’ high copper metabolic dependence, this strategy selectively induces cancer cell death with minimal normal tissue injury. The results of this study show significant tumor suppression and low systemic toxicity. In summary, our research introduces an innovative metabolic‐targeted nanotherapeutic approach, elucidating the synergistic effects between photothermal therapy and copper‐mediated mechanisms, which holds potential as a promising strategy for TNBC treatment.