Metformin-loaded multi-enzymatic metal-organic framework nanozyme mediates metabolic reprogramming via multiple energy blockades to boost tumor immunotherapy.

Abstract

Glycolytic metabolism of tumor cells suppresses the activity of immune cells, and multiple blocking energy supply and remodeling the metabolic microenvironment are important strategies to enhance immunotherapy. Using manganese-doped porphyrin metal-organic framework (MOF) as a carrier, by depositing ultrasmall Au nanoparticle (AuNPs), loading metformin (MET) and coating polydopamine (PDA), an integrated MOF@Au/MET@PDA nanozyme with multi-enzyme activity was constructed for enhancing antitumor immunotherapy. MOF@Au/MET@PDA nanozyme possessed glutathione peroxidase/glucose oxidase/peroxidase/catalase-like activity, by which the reactive oxygen species generation was greatly enhanced, and the mitochondrial function was damaged. Moreover, by consuming glucose and inhibiting the synthesis of adenosine triphosphate, the MOF@Au/MET@PDA nanozyme effectively blocked the energy supply and hindered glycolysis. Furthermore, the MOF@Au/MET@PDA nanozyme up-regulated the Caspase 3/7 level and down-regulated the expression of programmed death ligand-1, by which the apoptosis was induced and the immunogenic cell death was triggered. Under the combined immunotherapy, the immune response was activated, and the primary and metastatic tumors were greatly inhibited, proving the strong immune effect of MOF@Au/MET@PDA nanozyme. STATEMENT OF SIGNIFICANCE: Tumor metabolic plasticity undermines the efficacy of single-pathway immunotherapy. In this work, a multi-enzymatic MOF@Au/MET@PDA nanozyme is engineered to mediate metabolic reprogramming by blocking energy supply through glucose depletion and suppression of glycolysis/oxidative phosphorylation. It amplifies oxidative stress, triggers ICD, down-regulates PD-L1, and remodels the immunosuppressive microenvironment. This nanozyme effectively inhibits primary breast tumors and lung metastasis, providing a metabolic-reprogramming strategy to boost tumor immunotherapy.