A glucose-driven engineered glucose oxidase/Cu-based nanozyme composite for flipping the PKM2 lactylation “switch” toward amplified cuproptosis and enhanced cancer radiosensitivity

Cuproptosis is a type of programmed cell death that has been shown to significantly improve cancer radiosensitivity. The tumor microenvironment, characterized by glycolytic activity, suppresses cuproptosis, with the increase of pyruvate kinase M2 (PKM2) lactylation serving as the principal regulators of the switch to glycolysis in hypoxic tumor settings. To address this issue, we proposed a hypoxia-alleviation-driven strategy using a glucose-driven engineered glucose oxidase (GOx)/Cu-based nanozyme composite aimed at activating the PKM2 lactylation “switch” to enhance cuproptosis for improved cancer radiotherapy. This is accomplished through a dual-enzyme cuproptosis inducer featuring a self-supplying H 2 O 2 catalytic system, which co-encapsulates GOx and catalase-like copper sulfide nanoparticles (CuS NPs) within AS1411 aptamer-modified liposomes. GOx utilizes intratumoral glucose to generate H 2 O 2 , which is then converted into O 2 by CuS NPs, alleviating tumor hypoxia. The oxygenated microenvironment inhibits HIF-1α and PKM2 lactylation, altering metabolism from glycolysis to mitochondrial respiration. Flipping this metabolic “switch” amplifies Cu 2+ -mediated cuproptosis and increases cancer radiosensitivity, ultimately offering a novel approach for the clinical treatment of radioresistant cancers.