The TripartiteCascade Strategy AmplifiesCellular Oxidative Stress to DisruptOxidation–Reduction Homeostasis for Tumor Immunogenic CellDeath

Immunogenic cell death (ICD) induced by intracellular oxidation–reduction homeostasis imbalance is a classic mechanism in cancer immunotherapy. Herein, we propose a tripartite strategy to amplify cellular oxidative stress based on a combination of peptidic nanoparticles (TPF_NO/CCA NPs) of host–guest drug-loading, fibrillar transformation, and NO generation. Cinnamaldehyde (CA) was released from TPF_NO/CCA NPs due to Schiff base bond breakage within the lysosome, promoting excessive ROS generation. The residual TPF_NO/C NPs bind the mitochondria, where excessive ROS induces the host–guest disintegration of ferrocene/β-cyclodextrin. The β-sheet TPF_NO peptide could further transform into a fibrillar network on the mitochondria surface, leading to a further surge of ROS. Concurrently, the TPF_NO peptide would locally release NO gas by consuming intracellular glutathione. NO further reacts with ROS and yields ONOO^–, exacerbating mitochondrial dysfunction. Through a synergistic cascade of ROS generation and glutathione consumption, TPF_NO/CCA NPs efficiently amplify oxidative stress, inducing potent immunogenic death in tumor cells.