A trojan horse selenium-containing polymer for protective co-delivery of Fe(II) and cisplatin to boost chemo-ferroptosis synergy via GSH-triggered ROS storm

Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, is critically influenced by ferrous ions (Fe²⁺) and hydrogen peroxide (H₂O₂). However, the inherent instability of Fe²⁺ and insufficient levels of endogenous H₂O₂ within the tumor microenvironment necessitate the combination of current iron-based nanoparticles with other modalities to achieve effective cancer therapy. Herein, we designed a glutathione (GSH)-responsive selenium-containing polymeric nanoreactor co-loaded with Fe²⁺ and cisplatin. Selenium-containing polymers can effectively enhance the stability of both Fe²⁺ and cisplatin, and undergo cleavage in tumor cells with high GSH levels to achieve specific cisplatin and Fe²⁺ release, resulting in a substantial depletion of GSH and downregulation of glutathione peroxidase 4 (GPX-4). More interestingly, cisplatin not only serve as a chemotherapeutic drug, but also promote intracellular H₂O₂ generation to fuel the Fe²⁺-mediated Fenton reaction, thereby cascading chemotherapy and ferroptosis to effectively kill cancer cells. This GSH-activated selenium-polymer armored Fe²⁺/cisplatin cascade nanoreactor effectively disrupts the anti-ferroptosis system in cancer cells and continuously drives ferroptotic cell death. By overcoming the limitations of current ferroptosis-based cancer therapies, this approach holds great promise for the development of safe, efficient, and precisely controllable ferroptosis-based cancer therapies.