A glutathione-responsive sulfur dioxide polymer prodrug selectively induces ferroptosis in gastric cancer therapy.

Nanoparticle-induced ferroptosis has been proven to be an appealing strategy in cancer treatment. Previously, we reported the synthesis of an amphiphilic polymer prodrug of SO, mPEG-PLG(DNs), which could self-assemble to formulate nanoparticles (NP-DNs) and trigger cancer cell death by GSH consumption and SO release. In the current study, the potential mechanism of NP-DNs-induced cell death was further investigated. We demonstrated that NP-DNs exhibited efficient antitumor activity against gastric cancer ferroptosis. NP-DNs could selectively accelerate lipid peroxidation through GSH depletion and SO generation in gastric cancer cells. In addition, the NP-DNs-induced GPX4 reduction played a collaborative role in ferroptosis. Concurrently, evaluations revealed that NP-DNs not only exhibited excellent antitumor efficiency ferroptosis but also caused little systemic toxicity in mice. All the results showed that NP-DNs would be a promising prodrug in precision-targeted ferroptosis therapy.