Bi‐Target Nanomodulator for Glioma‐Associated Myeloid Cells Polarization by Inducing Pyroptosis and Regulating Tryptophan Metabolism to Reshape Immunosuppressive Microenvironment of IDH‐Mutant Gliomas

ABSTRACT Since 2‐hydroxyglutarate (2‐HG) released from isocitrate dehydrogenase (IDH)‐mutant gliomas results in the strong immunosuppressive tumor microenvironment (TME), the immunotherapy effect is unsatisfactory. In this work, we develop a hybridized cell membrane of glioma‐macrophage cells (GMM) camouflaged bi‐target nanomodulator (LNO@CH/Ca 3 (PO 4 ) 2 , LCC) comprised of LaNiO 3 (LNO) core and Ca 3 (PO 4 ) 2 shell loaded with the aryl hydrocarbon receptor (AhR) antagonist (CH223191, CH), which can synergistically modulate glioma‐associated myeloid cells (GAM) polarization by inducing pyroptosis and regulating tryptophan metabolism to enhance the efficacy of IDH‐mutant gliomas immunotherapy. The hybrid cell membrane endows LCC@GMM with good blood brain barrier (BBB) penetration as well as dual homing ability to tumor cells and GAM. LCC@GMM not only induces pyroptosis in tumor cells by the production of cytotoxic reactive oxygen species (ROS) and the released La 3 + but also regulates tryptophan metabolism in GAM via the released CH, effectively overcoming the immunosuppressive effects of IDH‐mutant gliomas. The bi‐target synergistic regulation of GAM reshapes the immunosuppressive TME of IDH‐mutant gliomas and offers a novel idea for immunotherapy of IDH‐mutant gliomas.