Antigen-specific T cell immunotherapy by in vivo mRNA delivery

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.