Bioinspired nanocatalytic tumor therapy by simultaneous reactive oxygen species generation enhancement and glutamine pathway-mediated glutathione depletion

Abstract

An insufficient intracellular H₂O₂ level and overexpressed glutathione (GSH) are still the major challenges for effective chemodynamic therapy (CDT). Inspired by the unique glutamine metabolism pathway in cancer cells, herein, intelligent nanocatalytic theranostics is used to enhance intracellular reactive oxygen species (ROS) accumulation via the production of H₂O₂ by a biomimetic nanozyme, and simultaneously reduce ROS consumption via the depression of GSH synthesis by the glutamine metabolic inhibitor. In this reactor, nano-sized Au and Fe₃O₄ coloaded dendritic mesoporous silica nanoparticles (DMSN-Au-Fe₃O₄) serve as the bifunctional nanozyme, where intracellular glucose is catalyzed into H₂O₂ by the glucose oxidase-mimicking Au nanoparticles and then immediately transformed into ˙OH by the peroxidase-like Fe₃O₄ nanoparticles. Then, CB839, the glutaminase (GLS) inhibitor, is grafted on the nanozyme, blocking the glutamine pathway and GSH biosynthesis. As a result, the as-designed nanoplatform with a three-pronged integration of Au-mediated H₂O₂ self-supply, Fe₃O₄-triggered Fenton-like reaction, and glutamine pathway-mediated GSH depletion significantly boosts the CDT efficacy, achieving remarkable and specific antitumor properties both in vitro and in vivo. This work not only paves a new way for rationally designing multi-functional nanozymes for achieving high therapeutic efficacy, but also provides new insights into the construction of bioinspired synergetic therapy by combining CDT and a key anticancer pathway.