A Triple‐Responsive Polymeric Prodrug Nanoplatform with Extracellular Ros Consumption and Intracellular H2O2 Self‐generation for Imaging‐Guided Tumor Chemo‐Ferroptosis‐Immunotherapy

Abstract High reactive oxygen species (ROS) levels in tumor microenvironment (TME) will impair both immunogenic cell death (ICD) efficacy and T cell activity. Furthermore, tumor escapes immunosurveillance via programmed death‐1/programmed death ligand‐1 (PD‐L1) signal, and the insufficient intracellular hydrogen peroxide will weaken ferroptosis efficacy. To tackle the above issues, we construct a glutathione (GSH)/ROS/pH triple‐responsive prodrug nanomedicine that encapsulates Fe 2 O 3 nanoparticle via electrostatic interaction for magnetic resonance imaging (MRI)‐guided multi‐mode theranostics with chemotherapy/ferroptosis /immunotherapy. The diselenide bond consumes ROS in TME to increase T cells and ICD efficacy, the cleavage of which facilitates PD‐L1 antagonist D peptide release to block immune checkpoint. After intracellular internalization, Fe 2 O 3 nanoparticle is released in the acidic endosome for MRI simultaneously with lipid peroxides generation for tumor ferroptosis. DOX is cleaved from polymers in the condition of high intracellular GSH level accompanied by tumor ICD, which simultaneously potentiates ferroptosis by NADPH oxidase mediated H 2 O 2 self‐generation. In vivo results indicate that the nanoplatform strengthens tumor ICD, induces cytotoxic T lymphocytes proliferation, inhibits 4T1 tumor regression and metastasis, and prolongs survival median. In all, we propose a new strategy in strengthening ICD and T cells activity cascade with ferroptosis as well as immune checkpoint blockade for effective tumor immunotherapy. This article is protected by copyright. All rights reserved