During autoimmunity, the body identifies and attacks “self” molecules as foreign. Current therapies employ broad immunosuppression, which is beneficial to patients, but can leave them immunocompromised. This limitation, along with the lack of cures, has sparked intense interest in strategies that could control autoimmunity with vaccine-like specificity, leaving the rest of the immune system intact. Several pre-clinical reports and clinical trials have investigated this theory to combat multiple sclerosis (MS), a neurodegenerative disease that impacts many Veterans and occurs when myelin in the central nervous system (CNS) is attacked by the immune system. An important finding from these studies is that co-administration of myelin peptide and tolerizing immune signals can promote the development of regulatory T cells (TREGS) that ameliorate disease. Interestingly, one set of pathways hindering control of myelin-driven inflammation are toll like receptors (TLRs). In healthy individuals, these pathways detect pathogen-associated patterns to support innate immunity. However, recent studies reveal that toll like receptor signaling – TLR9, for example – is elevated in human MS and in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Suppressing TLR9 function not only reduces inflammation, but also promotes TREGS and improves disease. Polarization of naïve, myelin-reactive T cells into inflammatory T cells (e.g., TH17) or TREGS is localized to spleen and lymph nodes (LNs), tissues that coordinate immunity. Thus, strategies that help program how T cells differentiate when myelin is presented in LNs – for example, delivering regulatory cues – could generate large populations of myelin-specific TREGS that stop pathogenic immune cells without broad suppression. Nanotechnology holds great promise in this area through increased control over targeting, release kinetics, and delivery of multiple signals. However, many polymer particles and other materials exhibit intrinsic features that activate inflammatory pathways, which could exacerbate autoimmune disease. Strategies that mimic attractive features of biomaterials, while eliminating inflammatory “carrier” effects could be transformative for new therapies for MS or other autoimmune diseases. Toward this goal, the proposed research will use polyionic immune signals to create novel nanostructured capsules built entirely from regulatory immune signals and myelin antigens. These immune polyelectrolyte multilayers (“iPEMs”) are assembled through electrostatic interactions on a template, which is then removed to leave vaccines capsules that juxtapose myelin and TLR9-suppressive nucleic acids (GpG). Since there is no carrier, the density of signals in iPEMs is very high relative to lipid or polymer formulations with cargo embedded in a matrix. Further, the particles condense the signals at high densities, a characteristic that could promote differentiation toward TREG through co-localization of m...