During autoimmune disease, the body identifies and attacks “self” molecules. Current therapies are not curative and require life-long compliance. Further, existing therapies – while beneficial, are broadly acting and can leave patients immunocompromised. These challenges have sparked great interest in controlling autoimmunity with vaccine-like specificity to preserve normal immune function. Both pre-clinical and clinical studies are testing this idea in multiple sclerosis (MS), a disease that disproportionality impacts Veterans. MS is a neurodegenerative disease driven by mistaken attack of myelin in the central nervous system (CNS). Thus, an experimental therapy idea involves co-administration of myelin peptide and tolerizing cues to promote myelin-specific regulatory T cells (TREG) that control MS. In some recent trials, small sets of 6-8 myelin epitopes are being tested as a route to span the range of myelin reactivity in many - though not all - patients. Interestingly, one set of pathways newly- associated with myelin-driven inflammation are toll-like receptors (TLRs). In healthy people, TLRs detect pathogen-associated patterns to mobilize innate immunity. However, new work shows TLR signaling - such as TLR9 - is elevated in MS patients and MS models (e.g., EAE, RR-EAE). In the latter, suppressing TLR9 function reduces inflammation, while also promoting TREG and improving disease. Lymph nodes (LNs) and spleen are key tissues that control polarization of myelin-reactive T cells toward either inflammatory T cells (e.g., TH17) or TREG. Thus, strategies that guide T cell differentiating when myelin is presented in LNs – for example, co-delivery of regulatory cues – could generate large populations of myelin-specific TREG that stop pathogenic immune cells without broad suppression. Nanotechnology offers unique capabilities for this goal, including co-delivery of self- antigen and regulatory cues, targeting, and tunable release. However, many polymer particles and other biomaterials exhibit intrinsic features that trigger inflammatory signaling, which could exacerbate autoimmunity. Strategies that mimic attractive features of biomaterials, while eliminating inflammatory “carrier” effects could be transformative for new therapies for MS. This Renewal VA Merit application uses polyionic immune signals to advance novel nanostructured capsules built entirely from regulatory immune cues and myelin antigen. These immune polyelectrolyte multilayers (“iPEMs”) are assembled through electrostatic interactions on a template, which is removed to leave capsules that juxtapose myelin with a regulatory TLR ligand against TLR9 (GpG). Since there is no carrier, the density of signals in iPEMs is very high relative to polymer or lipids encapsulating cargo (e.g., nanoparticles). During the initial award, this high density juxtaposition of self-antigen and regulatory cue (GpG) was shown to promote differentiation of myelin-specific T cells toward TREG and away from in...