HO self-supplying cascade catalytic nanoreactors amplify oxidative stress for augmented cuproptosis-driven multimodal synergistic therapy of breast cancer.

Cuproptosis, a newly identified form of programmed cell death, has exhibited great potential in the treatment of breast cancer. However, excess glutathione and inadequate hydrogen peroxide (HO) and poor Fenton reaction efficiency in tumor cells limit cuproptosis-photo-chemodynamic therapy effect. Herein, we developed a HO self-supplying cascade catalytic self-assembled nanoreactors (PGIC NPs) based on chemotherapeutic drug paclitaxel (PTX), natural enzyme glucose oxidase (GOx), metal copper ions (Cu) and photosensitizer indocyanine green (ICG) for cuproptosis-mediated chemo-photo-starvation-chemodynamic therapy. These multifunctional self-assembled nanoreactors with ideal particle size were more easily taken up by 4T1 cells. PGIC NPs could catalyze tumor-overexpressed glucose to achieve the self-supplying of HO to promote starvation therapy, cascade catalyze hydroxyl radical (·OH) production via Fenton-like reaction to facilitate chemodynamic therapy. These nanoparticles could not only consume GSH, induce a photothermal effect to strengthen the efficiency of Fenton-like reactors, promote the production of ·OH and singlet oxygen (O) to create a "ROS storm", augment oxidative stress; but also induce acylated protein oligomerization to trigger cuproptosis, leading to cuproptosis-driven chemo-photo-chemodynamic-starvation synergistic therapy. In vivo studies demonstrated that PGIC NPs showed good biosafety and could significantly inhibit the growth of 4T1 tumor-bearing mice. Overall, this study provided new insights into HO self-supplying cascade catalytic self-assembled nanoreactors to achieve cuproptosis-driven multimodal synergistic therapy of breast cancer.