H2O2 self-supplying cascade catalytic nanoreactors amplify oxidative stress for augmented cuproptosis-driven multimodal synergistic therapy of breast cancer

Abstract

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 (H₂O₂) and poor Fenton reaction efficiency in tumor cells limit cuproptosis-photo-chemodynamic therapy effect. Herein, we developed a H₂O₂ self-supplying cascade catalytic self-assembled nanoreactors (PGIC NPs) based on chemotherapeutic drug paclitaxel (PTX), natural enzyme glucose oxidase (GOx), metal copper ions (Cu²⁺) 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 H₂O₂ 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 (¹O₂) 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 H₂O₂ self-supplying cascade catalytic self-assembled nanoreactors to achieve cuproptosis-driven multimodal synergistic therapy of breast cancer.