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

• Published in: Chemical engineering journal (Lausanne, Switzerland : 1996) Switzerland : 1996), 2024-12, Vol.501, p.157762, Article 157762
• Main Authors: Yin, Yipengchen, Zhu, Li, Jiang, Tiaoyan, Chai, Rong, Zhang, Ya, Li, Tianyu, Wang, Kai, Wang, Sheng, Zhang, Qin
• Format: Article
• Language: English
• Subjects: Enzyodynamic therapy; Ferroptosis; Nanozyme; Radiaotherapy; Two-dimensional bismuthene
• ISSN: 1385-8947
• DOI: 10.1016/j.cej.2024.157762

Synthesis and therapeutic illustrations of BMBs. (a) Synthetic process for BMBs. (b) Schematic illustration of enhanced ferroptotic radiotherapy induced by BMBs. [Display omitted] •2D-BNs were successfully prepared via ultrafacile sonicate-freeze–thaw cycles and modified with BSA and MnOx to fabricate BMBs.•BMBs were characterized by homogeneous size (∼200 nm), superior biosafety and satisfactory biocompatibility.•BMBs present a multienzyme-like nanoplatform enabled enzyodynamic therapy and synergistic ferroptosis/radiosensitization against cancer. 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.