Abstract

Background:Glioblastoma (GBM) has emerged as a model of resistance to immunotherapy because of the immunosuppressive tumor microenvironment (TME), which is closely associated with tryptophan metabolism. Inhibiting the expression of indoleamine 2,3-dioxygenase-1 (IDO1, a key enzyme in tryptophan metabolism) is a promising strategy for improving the immunosuppressive TME. Meanwhile, Gasdermin B (GSDMB)-mediated pyroptosis is a newly identified mechanism for activating the immune response.Methods:We prepared a GBM cell membrane (CM)-modified lipid nanoparticle (CMLNP) to deliver CRISPR/Cas9 components and mRNA encoding the N-terminal domain of GSDMB (GSDMBNTmRNA).Results:The CM modification endowed the LNP with a tumor homing/homotypic targeting effect. Then, CRISPR/Cas9 components realized the knockdown of theIDO1gene, thus remodeling the TME. GSDMBNTmRNA triggers pyroptosis, thus eliciting an immune response.Conclusions:This system generated potent antitumor immunity and offered a novel strategy for GBM immunotherapy.