PROJECT SUMMARY Multiple sclerosis (MS) is the leading cause of non-traumatic disability in young adults in the United States. In MS, the immune system attacks autoantigens in the myelin sheath of the central nervous system (CNS), leading to neurological degeneration, and there is currently no cure. A treatment for MS that does not cause general immunosuppression is urgently needed. One leading strategy for this is to induce antigen-specific immune tolerance, which can prevent immune responses against the myelin sheath without having a systemic suppressive effect. In order to accomplish this, we propose to use synthetic, biodegradable polymeric nanoparticles to deliver mRNA encoding the MS autoantigen myelin oligodendrocyte glycoprotein (MOG) to antigen-presenting cells (APCs) as a tolerogenic nanoparticle (NP)-based vaccine. By engineering the NPs to selectively target the liver, where APCs express low levels of activating signals and surrounding cells secrete high concentrations of immunosuppressive signals, we will enable presentation of the MOG antigen to T cells in a tolerogenic context. As a second layer of safety to prevent inadvertent immune stimulation targeting the MOG antigen, we will co-deliver an immunosuppressive agent. This is designed to lead to expansion of MOG-specific regulatory T cells (Tregs), which will provide antigen-specific protective immunosuppression. At the same time, in the absence of activating co-stimulatory molecules, the transfected APCs can also cause anergy or death of MOG-specific Th1, Th17, and CD8+ T cells, thereby preventing such cells from causing disease. This proposal will further optimize the NP formulations to maximize APC transfection, minimize unintended immune activation, and further improve in vivo delivery of NPs selectively. This NP technology represents an innovative vaccine platform for preventing or treating MS, with advantages of safety and ease of manufacture compared to other related technologies, such as the use of viral vectors for gene delivery.