Cell Membrane-Modified Lipid Nanoparticle Enhanced Glioblastoma Immunotherapy via Metabolism Reprogramming and Pyroptosis Induction

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 (GSDMBNT mRNA). Results: The CM modification endowed the LNP with a tumor homing/homotypic targeting effect. Then, CRISPR/Cas9 components realized the knockdown of the IDO1 gene, thus remodeling the TME. GSDMBNT mRNA triggers pyroptosis, thus eliciting an immune response. Conclusions: This system generated potent antitumor immunity and offered a novel strategy for GBM immunotherapy.