Engineered multienzyme-mimicking 2D bismuthene catalytic nanotriggers enable cascade enzyodynamic-boosted and synergistic GPX4/FSP1-mediated ferroptosis amplification for cancer radiosensitization

Radiotherapy (RT) is a critical clinical treatment for cancer. However, radioresistance often hampers its effectiveness, leading to local recurrence and therapeutic failure. Ferroptosis has been regarded as a natural barrier to tumor progression and plays a significant role in RT-mediated anticancer effects. Therefore, the simultaneous activation of ferroptosis and RT is of great significance for cancer therapy. Herein, we engineered the tumor-releasing nanozymes (BMBs), combining manganese oxide as the ferroptosis inducer and two-dimensional bismuthene with high-Z effect for augmented ferroptotic RT in a triple-enzyme-like radiosensitization manner. The nanozymes BMBs depleted glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH) in the tumor microenvironment to exhibit glutathione peroxidase (GPX)-like activity and NADPH dehydrogenase (NDH)-like activity, accompanied by aberrant reactive oxygen species (ROS) production exhibiting peoxidase (POD)-like activity. In addition, the nanozymes BMBs simultaneously inactivate ferroptosis defensive system: glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) to induce ferroptosis. The strong oxidative stress induced cascade enzyodynamic effect and ferroptosis, which synergized with the two-dimensional bismuthene-mediated radiosensitization to improve the efficacy of RT. Both in vitro and in vivo experiments substantiated the excellent radiotherapeutic response of the nanozymes by enhancing RT and ferroptosis. Therefore, this work demonstrates that the rational combination of nanozymes with POD/GPX/NDH-like activity and GPX4/FSP1 suppressing ability to induce ferroptosis for synergistic radiosensitization provides a viable and promising strategy for cancer treatment.