Enhanced Cuproptosis via Metabolic Reprogramming Using Copper-Delivering Co–N–C Single-Atom Nanozyme

Cuproptosis, a copper-dependent cell death, has shown promise as a cancer therapy characterized by mitochondrial protein aggregation. However, this distinct feature makes its efficacy highly dependent on the metabolic state of cancer cells, yielding poor outcomes in hypoxic tumors with a reduced mitochondrial activity. Herein, we construct a Cu-delivering vehicle with catalase-like activity using oxygen-rich cobalt single-atom nanozymes (Cu@CoNC(O)) to reprogram metabolism while delivering copper. By introduction of oxygen-containing functional groups onto carbon supports, Cu@CoNC(O) exhibits significantly improved loading efficiency of Cu ions compared to its oxygen-deficient counterpart. Simultaneously, the outstanding catalase-like activity of Cu@CoNC(O) alleviates hypoxia, switching metabolism from glycolysis to mitochondrial respiration through the inhibition of lactate metabolism and activation of the pyruvate dehydrogenase complex. The synergistic effect of the metabolic shift and efficient Cu delivery promotes cuproptosis even under hypoxic conditions, leading to enhanced therapeutic effects. This study demonstrates the potential of single-atom nanozymes as catalytic ion delivery vehicles capable of concurrently performing catalytic functions and delivering metal ions, presenting an effective strategy to enhance cuproptosis through metabolic modulation.