Multifunctional RGD coated a single-atom iron nanozyme: A highly selective approach to inducing ferroptosis and enhancing immunotherapy for pancreatic cancer

Nanozyme is a new promising approach to cancer therapy for its ability to induce ferroptosis by activating H₂O₂ via a traditional radical pathway and enhance cancer immunotherapy. However, short half-life period of hydroxyl radical (·OH) results in unsatisfied effectiveness. Herein, we synthesized a single-atom iron nanozyme (Fe-SAzyme), which can activate H₂O₂ via a non-radical pathway to generate Fe-based reactive oxygen species (ROS) (O=FeO₃=O) for promoting the ferroptosis of pancreatic cancer cells. This Fe-SAzyme could be specifically phagocytosed by pancreatic cancer cells, increasing ROS levels and inhibiting glutathione (GSH) synthesis, which activates ferroptosis. Tumor magnetic resonance imaging (MRI) showed decreased T2 signal after intravenous injection of RGD@Fe-AC (AC = activated carbon). Moreover, RGD@Fe-AC promoted dendritic cell (DC) maturation, overcame Treg-mediated immunosuppression, activated T cells to trigger adaptive immune responses, and enhanced the efficacy of α-PD-L1 immunotherapy. Our research demonstrated that RGD@Fe-AC provided a straightforward, easily implemented, and selective approach for pancreatic cancer treatment and immunotherapy.