mRNA–Lipid Nanoparticle Platforms for Antigen-Specific Immune Tolerance in Peanut and Food Allergy

Peanut allergy is a severe and persistent IgE-mediated disease for which current immunotherapies primarily achieve transient desensitization rather than durable immune regulation. Recent advances in lipid nanoparticle (LNP)-mediated mRNA delivery have enabled development of tolerogenic nanomedicine platforms that exploit the liver’s intrinsic capacity for antigen-specific immune conditioning, particularly through antigen presentation by liver sinusoidal endothelial cells (LSECs) and associated induction of regulatory CD4+ T-cell responses. A central safety feature of these approaches is the use of defined, non-IgE-binding allergen epitopes rather than intact allergenic proteins, thereby minimizing the risk of mast-cell activation while enabling controlled systemic antigen presentation. Emerging preclinical studies using epitope-encoded mRNA–LNP systems have demonstrated suppression of peanut-induced anaphylaxis together with attenuation of Th2-associated immune pathways, expansion of Foxp3+ regulatory T-cells, and increased production of tolerogenic cytokines, including IL-10 and TGF-β. Protection observed across repeated allergen challenge and resensitization settings, as well as adoptive-transfer studies, supports the possibility of durable regulatory immune programming. Therapeutic performance is closely linked to nanomaterial engineering parameters, including epitope composition, intracellular antigen-routing design, mRNA dose, and hepatic biodistribution, which collectively shape antigen presentation context and downstream immune responses. These programmable design features further support incorporation of multiple epitopes and potential application to poly allergen and mixed food sensitization states. This Perspective examines the mechanistic and engineering principles underlying liver-targeted tolerogenic mRNA–LNP platforms and discusses their emerging potential as antigen-specific immunotherapies for food allergy and related allergic diseases.