Diselenide‐Containing Polymer Based on New Antitumor Mechanism as Efficient GSH Depletion Agent for Ferroptosis Therapy

Abstract Glutathione (GSH) depletion‐induced ferroptosis has emerged as a promising treatment for malignant cancer. It works by inactivating glutathione peroxidase 4 (GPX4) and facilitating lipid peroxidation. However, effectively delivering inducers and depleting intracellular GSH remains challenging due to the short half‐lives and high hydrophobicity of small‐molecule ferroptosis inducers. These inducers often require additional carriers. Herein, diselenide‐containing polymers can consume GSH to induce ferroptosis for pancreatic cancer therapy. The diselenide bonds are controllably built into the backbone of the polycarbonate with a targeting peptide CRGD (Cys‐Arg‐Gly‐Asp), which allows for self‐assembly into stable nanoparticles (denoted CRNSe) for self‐delivery. Significantly, at a concentration of 12 µg mL −1 , CRNSe binds to the active site cysteine of GSH resulting in a thorough depletion of GSH. In contrast, the disulfide‐containing analog only causes a slight decrease in GSH level. Moreover, the depletion of GSH inactivates GPX4, ultimately inducing ferroptosis due to the accumulation of lipid peroxide in BxPC‐3 cells. Both in vitro and in vivo studies have demonstrated that CRNSe exhibits potent tumor suppressive ability with few side effects on normal tissue. This study validates the anti‐tumor mechanism of diselenide‐containing polymers in addition to apoptosis and also provides a new strategy for inherently inducing ferroptosis in cancer therapy.