Glutathione-Responsive Polymeric Nanosystem for the Codelivery of Iron and Doxorubicin to Promote Synergistic Ferroptosis and Chemotherapy in Cancer Treatment

Effective cancer therapy remains challenging due to poor tumor specificity, low drug bioavailability, and systemic toxicity of conventional treatments. Herein, we develop a glutathione (GSH)-responsive nanodrug, PEG-SS-PCL@Fe-DOX, which synergistically combines ferroptosis and chemotherapy to achieve enhanced antitumor efficacy. This nanosystem employs a disulfide-linked amphiphilic polymer (PEG-SS-PCL) to encapsulate the Fe-DOX complex, enabling GSH-triggered, tumor-specific drug release. In the tumor microenvironment, cleavage of disulfide bonds facilitates the release of DOX and Fe²⁺, where DOX intercalates into DNA to inhibit proliferation, and Fe²⁺ catalyzes Fenton reactions and suppresses GPX4 activity, collectively inducing excessive reactive oxygen species production and ferroptosis. This synergistic mechanism markedly improves therapeutic efficiency, offering a promising strategy for precise and effective cancer treatment.