Abstract
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 Fe(2+), where DOX intercalates into DNA to inhibit proliferation, and Fe(2+) 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.