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Published on: September 27, 2024
Cell Membrane-Modified Lipid Nanoparticle Enhanced Glioblastoma Immunotherapy via Metabolism Reprogramming and
Pengxuan Zhao1,2, Yu Tian3, Weigang Yuan4
1Hainan Provincial Key Laboratory of Research and Development on Tropical Herbs, Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, School of Pharmacy, Hainan Medical University, Haikou 571199, China.
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 (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.
