TME-triggered MnSiO3@Met@GOx nanosystem for ATP dual-inhibited starvation/chemodynamic synergistic therapy

Adenosine triphosphate (ATP) is an essential substance for maintaining tumor cell survival and proliferation. Inhibiting the ATP-producing pathways has emerged as a promising cancer treatment strategy. However, the antitumor efficiency of ATP inhibitors is compromised by the inter-compensation of multiple ATP-producing pathways in tumor cells and biological barriers in the complex tumor microenvironment (TME). Herein, we developed metformin (Met) and glucose oxidase (GOx) co-loaded manganese silicon nanoplatform MnSiO3@Met@GOx (MMG) for TME-responsive ATP dual inhibited starvation/chemodynamic synergistic therapy. Under the mildly acidic conditions in TME, MMG was decomposed, releasing Met and GOx for effective ATP suppression by inhibiting oxidative phosphorylation (OXPHOS) and aerobic glycolysis pathways, respectively. Meanwhile, GOx-catalyzed glucose oxidation increased tumor acidity and hydrogen peroxide (H2O2) concentration in tumors, which not only accelerated MMG decomposition and drug release but also promoted manganese ions-mediated Fenton-like reaction. In vitro and in vivo experiments further demonstrated the effectiveness and biosafety of MMG-based synergistic therapy. This study provides a novel strategy for tumor treatment based on tumor metabolism regulation.