MnPt@metal organic framework nanozyme with photothermal/catalytic dual-strategy enhances Zn2+-mediated immunotherapy through activating pyroptosis and cGAS-STING pathway

Abstract Zinc ions (Zn2+) can induce immune response through activating pyroptosis and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, and disrupting the intracellular redox balance is an important strategy for enhancing Zn2+-driven immunotherapy. Herein, using bimetallic manganese platinum (MnPt) nanozyme as the core, a multifunctional MnPt@ZIF-8/β-Lap@F-127 nanozyme with multi-enzyme activity was developed by coating metal-organic framework (ZIF-8), carrying β-lapachone (β-Lap) and modifying F-127, and the Zn2+-induced immunotherapy was enhanced through photothermal/catalytic dual-strategy. The MnPt@ZIF-8/β-Lap@F-127 nanozyme has the glutathione peroxidase/peroxidase/catalase-like activity, and the photothermal and photoacoustic imaging properties. Under acidic microenvironment, the MnPt@ZIF-8/β-Lap@F-127 nanozyme was degraded and the Zn2+ and β-Lap were released. By producing a large amount of reactive oxygen species, the MnPt@ZIF-8/β-Lap@F-127 nanozyme induced apoptosis and pyroptosis, and activated the cGAS-STING pathway. Under the dual action of photothermal/catalytic, the mitochondrial function was destroyed, and the damage-related molecular patterns were released, effectively triggering the immunogenic cell death. By improving the immune cells infiltration and pro-inflammatory factors level, and reducing the immunosuppressive cells proportion, the MnPt@ZIF-8/β-Lap@F-127 nanozyme greatly inhibited the primary tumor growth and lung metastasis, which demonstrated that the MnPt@ZIF-8/β-Lap@F-127 nanozyme remodeled the immune microenvironment and enhanced the Zn2+-induced immunotherapy.