Controllable Synthesis of Fe2+-Rich Nanoworms for Combined Tumor Therapy Based on Ferroptosis and Immunotherapy

Ferroptosis is an immunogenic form of cell death characterized by iron-dependent lipid peroxidation. The balance between Fe2+ and Fe3+ is crucial in inducing ferroptosis, where Fe2+ primarily initiates the Fenton reaction to generate reactive oxygen species (ROS), resulting in lipid peroxidation and subsequent cell damage. However, the instability of Fe2+, due to its susceptibility to oxidation into Fe3+, poses challenges for effectively triggering ferroptosis. In this study, we report a synthetic method for creating Fe2+-rich nanoworms regulated by oleyl amine, which effectively stabilizes Fe2+. These nanoworms exhibited exceptional efficacy in producing ROS through high Fe2+ proportion and glutathione (GSH) consumption by Fe3+, thereby initiating lipid peroxidation (LPO) and subsequent induction of ferroptosis and immunogenic cell death. The conjugation with tumor-penetrating peptide (iRGD) endowed the accumulation at tumor sites. After coupling with αPD-L1, these nanoworms significantly enhanced their tumor inhibition rate through the combination of ferroptosis and immunotherapy, reducing the tumor volume to 22.52%. This work provides a promising material for combined tumor therapy by inducing ferroptosis and downstream immunotherapy.