The Tripartite Cascade Strategy Amplifies Cellular Oxidative Stress to Disrupt Oxidation–Reduction Homeostasis for Tumor Immunogenic Cell Death

• Published in: ACS materials letters Vol. 7; no. 3; pp. 730 - 740
• Main Authors: Jiang, Lingdong, Chen, Xiaojia, Gu, Yuqing, Deng, Fuan, Song, Yue, Mao, Chunping, Tong, Yuqi, Wang, Fengyi, Zhang, Wenyuan, Liu, Yujing, Chen, Yichi, Shi, Haonan, Zhang, Lu
• Format: Journal Article
• Language: English
• Published: American Chemical Society 03.03.2025
• DOI: 10.1021/acsmaterialslett.4c02423
• ISSN: 2639-4979

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 (TPFNO/CCA NPs) of host–guest drug-loading, fibrillar transformation, and NO generation. Cinnamaldehyde (CA) was released from TPFNO/CCA NPs due to Schiff base bond breakage within the lysosome, promoting excessive ROS generation. The residual TPFNO/C NPs bind the mitochondria, where excessive ROS induces the host–guest disintegration of ferrocene/β-cyclodextrin. The β-sheet TPFNO peptide could further transform into a fibrillar network on the mitochondria surface, leading to a further surge of ROS. Concurrently, the TPFNO 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, TPFNO/CCA NPs efficiently amplify oxidative stress, inducing potent immunogenic death in tumor cells.