Delivery of a GPX4 Inhibitor by SN38 Prodrug Nanoassemblies for Amplified Antitumor Efficacy Based on Ferroptotic Chemotherapy

Prodrug‐based self‐assembled nanoassemblies, with carrier‐free structures and high drug loading, are garnering attention for chemotherapy. Additionally, the synergistic effects of prodrug nanoassemblies combined with multiple cell death pathways deserve further exploration. Ferroptosis has emerged as a powerful nonapoptotic cell death modality, showing significant potential for tumor inhibition. Therefore, prodrug nanoassemblies combined with ferroptosis inducers may achieve amplified antitumor efficacy. Herein, a GPX4 inhibitor (ML210)‐loaded SN38 prodrug nanoparticle system is developed to enhance antitumor efficacy via ferroptotic‐chemotherapy synergy. In this system, SN38 is conjugated to 1‐octadecanol by a disulfide linkage to construct the self‐assembly prodrug. DSPE‐PEG 2k is applied to stabilize nanoassemblies. It is proven that ML210 is successfully encapsulated into the SN38 prodrug nanoassemblies by the one‐step precipitation method. Both prodrug nanoassemblies exhibit good stability and a GSH‐responsive release profile. Furthermore, ML210‐loaded nanoassemblies show stronger cytotoxicity, greater proliferation inhibition, and obvious ferroptosis activation. In the CT26 mouse model, ML210‐loaded prodrug nanoassemblies demonstrated superior antitumor effects. The strategy—using prodrug as “carriers” for ferroptosis inducers—offers a promising approach for synergistic antitumor therapy.