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 a…