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Copper-dependent cell death is a type of cell death reliant on copper, which has shown potential as a cancer therapy characterized by mitochondrial protein aggregation. However, this unique feature makes its effectiveness highly dependent on the metabolic state of cancer cells, leading to poor outcomes in hypoxic tumors with reduced mitochondrial activity.Here, we used an oxygen-rich cobalt single-atom nanozyme (Cu@CoNC(O)) to construct a Cu delivery carrier with peroxidase-like activity, aiming to reprogram metabolism while delivering copper.By introducing oxygen-containing functional groups onto the carbon support, the Cu@CoNC(O) shows a significantly higher loading efficiency of Cu ions compared to the oxygen-deficient counterpart. Meanwhile, the excellent catalase-like activity of Cu@CoNC(O) can alleviate hypoxia, shifting metabolism from glycolysis to mitochondrial respiration by inhibiting lactate metabolism and activating the pyruvate dehydrogenase complex.Even under hypoxic conditions, the synergistic effect of metabolic reprogramming and efficient Cu delivery can promote cuproptosis, thereby enhancing therapeutic efficacy. This study demonstrates the potential of single-atom nanozymes as catalytic ion delivery carriers, capable of performing both catalytic functions and metal ion delivery, proposing an effective strategy to enhance cuproptosis through metabolic regulation.

Biomedical Applications

This nanozyme platform, through a metabolic reprogramming strategy, preferentially targets tumors with mitochondrial abnormalities or glycolysis dependence (such as pancreatic cancer, liver cancer, and breast cancer), and enhances the efficacy when combined with radiotherapy/chemotherapy or photothermal therapy.It combines diagnostic and therapeutic functions (such as PET imaging with copper-based single-atom nanozymes), enabling real-time monitoring of carrier distribution and metabolic changes for precise intervention; its applications are expanded to the treatment of metabolism-related diseases, including neurodegenerative diseases (regulating energy metabolism/metal homeostasis), ischemia-reperfusion injury (improving hypoxia/metabolic disorders), and fibrotic/infectious diseases (modulating metabolic reprogramming).

Original link

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

ACS Nano ( IF 16 )

Pub Date : 2025-06-11

DOI: 10.1021/acsnano.5c00012

Kang Kim,  Jaewoo Lee,  Ok Kyu Park,  Hyochul Lee,  Taekyu Jang,  Jungho Kim, Bowon Lee,  Jeong Hyun Kim,  Jaeho Moon,  Seoin Back,  Nohyun Lee,  Seung Hong Choi,  Taeghwan Hyeo