LipoTAME · Harnessing engineered lipid nanoparticles to tame autoimmune neuroinflammation by inducing regulatory T cells through CNS myeloid reprogramming

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS), driven by autoreactive T cells that attack myelin and trigger relapsing-remitting inflammation and progressive neurodegeneration. Current therapies rely on systemic immunosuppression, which mitigates disease activity but fails to restore antigen-specific tolerance, underscoring the urgent need for site-specific reprogramming within the CNS. As brain border regions, including the choroid plexus (ChP) and ventricular interfaces, serve as key immune gateways for T cell trafficking within the CNS, we hypothesize local antigen presenting cells (APCs) can reprogram T cells. Among these APCs, Kolmer cells, recently characterized microglia-like cells at the ChP epithelium, represent an unexplored regulatory population with unique potential to modulate adaptive immunity at CNS entry sites. The LipoTAME project seeks to establish a first-in-class therapeutic strategy to induce local, antigen-specific tolerance by targeting Kolmer cells and paraventricular microglia with engineered lipid nanoparticles (LNPs). LNPs will carry nucleoside-modified mRNA encoding myelin antigens and tolerogenic cytokines, with the goal of reprogramming myeloid–T cell interactions and restoring regulatory T cell (Treg) function. In vivo proof-of-concept data from the host lab confirm efficient uptake of intraventricular LNPs by myeloid cells, demonstrating the approach’s feasibility. By integrating nanomedicine and neuroimmunology, LipoTAME aims to restore CNS-targeted immune tolerance in MS, with broad potential across autoimmune diseases. My expertise in ChP biology, including barrier properties and resident immune populations across health and disease, combined with Movahedi Lab’s cutting-edge platforms in CNS-targeted immunology and single-cell –omics, provides a strong foundation for LipoTAME to explore this novel approach and advance CNS-targeted immunotherapies.