mRNA Lipid Nanoparticles for <i>Ex Vivo</i> Engineering of Immunosuppressive T Cells for Autoimmunity Therapies.

Abstract

Cell-based therapies for autoimmune diseases have gained significant traction, with several approaches centered around the regulatory T (T_reg) cell─a well-known immunosuppressive cell characterized by its expression of the transcription factor Foxp3. Unfortunately, due to low numbers of T_reg cells available in circulation, harvesting and culturing T_reg cells remains a challenge. It has been reported that engineering Foxp3 expression in CD4⁺ T cells can result in a T_reg-like phenotype; however, current methods result in the inefficient engineering of these cells. Here, we develop an ionizable lipid nanoparticle (LNP) platform to effectively deliver Foxp3 mRNA to CD4⁺ T cells. We successfully engineer CD4⁺ T cells into Foxp3-T (FP3T) cells that transiently exhibit an immunosuppressive phenotype and functionally suppress the proliferation of effector T cells. These results demonstrate the promise of an LNP platform for engineering immunosuppressive T cells with potential applications in autoimmunity therapies.