Monitoring ROS Responsive Fe3O4‐based Nanoparticle Mediated Ferroptosis&Immunotherapy via 129Xe MRI

Abstract The immune checkpoint blockade strategy has improved the survival rate of late‐stage lung cancer patients. However, the low immune response rate limits the immunotherapy efficiency. Here, we report a ROS‐responsive Fe 3 O 4 ‐based nanoparticle that undergoes charge reversal and disassembly in the tumor microenvironment, enhancing the uptake of Fe 3 O 4 by tumor cells and triggering a more severe ferroptosis. In the tumor microenvironment, the nanoparticle rapidly disassembles and releases the loaded GOx and the immune‐activating peptide Tuftsin under overexpressed H 2 O 2 . GOx can consume the glucose of tumor cells and generate more H 2 O 2 , promoting the disassembly of the nanoparticle and drug release, thereby enhancing the therapeutic effect of ferroptosis. Combined with Tuftsin, it can more effectively reverse the immune‐suppressive microenvironment and promote the recruitment of effector T cells in tumor tissues. Ultimately, in combination with α‐PD‐L1, there is significant inhibition of the growth of lung metastases. Additionally, the hyperpolarized 129 Xe method has been used to evaluate the Fe 3 O 4 nanoparticle‐mediated immunotherapy, where the ventilation defects in lung metastases have been significantly improved with complete lung structure and function recovered. The ferroptosis‐enhanced immunotherapy combined with non‐radiation evaluation methodology paves a new way for designing novel theranostic agents for cancer therapy.