A nanoagent based on a supramolecular copper chelator for cancer therapy via copper depletion and glucose deprivation

Given the copper dependence of malignancies, copper depletion therapy has emerged as a promising anticancer strategy. However, its efficacy is hampered by the metabolic adaptability of tumors, which allows tumor cells switch their metabolic phenotype towards glycolysis to compensate for energy loss. Herein, we developed a glucose oxidase (GOx)-integrated nanoagent (designated as GDP NPs) using a supramolecular copper chelator (denoted as DP NPs) as the backbone. This nanoagent enables the simultaneous intracellular depletion of copper and deprivation of glycolytic substrates. The supramolecular chelator itself is formed via the self-assembly of 2,2′-dipicolylamine-perfunctionalized pillararene; it depletes copper to amplify oxidative stress and reduce adenosine triphosphate production. Concurrently, GOx disrupts the compensatory glycolytic pathway induced by copper depletion through the catalytic breakdown of glucose. Compared with copper depletion monotherapy, the combined effect of copper depletion and metabolic compensation blockade leads to an energy crisis in tumor cells. In vivo experimental results demonstrate that GDP NPs exhibit superior anticancer efficacy relative to DP NPs. Our work presents a novel supramolecular chemistry-based strategy for the concurrent depletion of copper and interference with metabolism, which overcomes the limitation of copper depletion monotherapy due to tumor metabolic adaptability.