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Antigen-specific T cell immunotherapy by in vivo mRNA delivery

Su, F.-Y.; Siebart, J. C.; Chan, C. S.; Wang, M. Y.; Yao, X.; Trenkle, A. D. S.; Sivakumar, A.; Su, M.; Harandi, R.; Shahrawat, N.; Nguyen, C. H.; Goenka, A.; Mun, J.; Dhodapkar, M. V.; Kwong, G. A.

2024-11-03 bioengineering
10.1101/2024.10.29.620946 bioRxiv
Show abstract

Immunotherapy has shown promise for treating patients with autoimmune diseases or cancer, yet treatment is associated with adverse effects associated with global activation or suppression of T cell immunity. Here, we developed antigen-presenting nanoparticles (APNs) to selectively engineer disease antigen (Ag)-specific T cells by in vivo mRNA delivery. APNs consist of a lipid nanoparticle core functionalized with peptide-major histocompatibility complexes (pMHCs), facilitating antigen-specific T cell transfection through cognate T cell receptor-mediated endocytosis. In mouse models of type 1 diabetes and multiple myeloma, APNs selectively deplete autoreactive T cells leading to durable control of glycemia, and engineer virus-specific T cells with anti-cancer chimeric antigen receptors (CARs), achieving comparable therapeutic outcome as virally transduced ex vivo CAR. Overall, our work supports the use of APNs to engineer disease-relevant T cells in vivo as Ag-specific immunotherapy for autoimmune disorders and cancer.

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