ATP‐Assisted Electron and Proton Transfer Boosting Redox Metabolism‐Induced Ferroptosis and Apoptosis for Cancer Therapy

Abstract

Abstract Compared to the intractability of traditional apoptosis, the vulnerability exposed by cancer cell metabolic reprogramming provides an advantage for ferroptosis treatment. Herein, we developed vanadate and aurintricarboxylic acid coordination nanoparticles (VAP NPs) that synergistically trigger dual cell death pathways. This nanoplatform leveraged dual‐Russell mechanisms and Fenton reactions to generate singlet oxygen/hydroxyl radicals in the tumor microenvironment (TME) while depleting glutathione via vanadium redox cycling, thereby silencing glutathione peroxidase 4 and modulating the Kelch‐like ECH‐associated protein 1 (KEAP1)/nuclear factor erythroid 2‐related factor 2 (NRF2)/heme oxygenase 1 (HMOX1) axis. Notably, TME‐overexpressed adenosine triphosphate (ATP) acted as a biochemical catalyst, accelerating the transfer of protons and electrons during reactive oxygen species generation to amplify therapeutic efficacy. Therefore, VAP NPs could achieve outstanding efficacy for intrinsically stimulated synergy of ferroptosis and apoptosis in tumor therapy. This study provides reference for revealing the new function of ATP in enhancing the regulation of redox metabolism.