Atovaquone-Coordinated Copper-Polyphenol Nanoplatform Orchestrates Dual Metabolic Interference for Synergistic Cuproptosis and Apoptosis.

Cuproptosis, a copper-dependent cell death mechanism, is hindered by tumor microenvironment (TME)-driven resistance including glutathione (GSH)-mediated copper detoxification and hypoxia-induced metabolic adaptation. We propose a "dual metabolic interference" strategy to amplify cuproptosis by synergistically targeting iron-sulfur (Fe-S) cluster proteins and suppressing oxidative phosphorylation (OXPHOS). A TME-responsive nanoplatform (ACH NPs) was constructed based on a copper-shikonin coordination network (CuSK), the OXPHOS inhibitor atovaquone (ATO), and hyaluronic acid (HA). Upon GSH/acid-triggered release, Cu/Cu and ATO/SK synergistically induced irreversible damage: (1) Copper overload induces dihydrolipoamide transacetylase (DLAT) aggregation and irreversible Fe-S cluster loss, directly disrupting mitochondrial complexes I-III functions; (2) ATO further suppresses complex III activity, reducing oxygen consumption and blocking ATP synthesis to exacerbate metabolic crisis; (3) Concurrently, Cu-catalyzed Fenton-like reactions synergize with SK-driven oxidative stress to generate •OH radicals, activating Caspase-3-dependent apoptosis. In vivo experiments verified that this dual metabolic interference strategy effectively inhibited tumor growth (86.8% tumor suppression). These findings not only expand the theoretical boundaries of cuproptosis but also establish a promising paradigm for cancer therapy through coordinated targeting of metal homeostasis and metabolic vulnerabilities.