Antigen-Specific Inverse Vaccination Strategies Using Particle Systems for Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that affects approximately 2.8 million people worldwide. In the United States alone, approximately 150 in every 100,000 people will develop MS ( Dilokthornsakul, P., et al. <i>Neurology</i> 2016, <b>86</b> (11), 1014-1021). In patients with MS, the myelin sheath, which serves as the insulation for the CNS, is attacked, resulting in the exposure of nerve fibers. The current standard of care for MS is centered around Disease-Modifying Treatments (DMTs) that work to increase the time between MS relapses. FDA-approved DMTs suppress the immune system in a nonspecific manner, putting patients at an increased risk of infections and adverse side effects. Inverse vaccination offers an antigen-specific alternative, aiming to induce immune tolerance to self-antigens without compromising general immune function. This means that the immune system has a reduced or unresponsive response to only the autoimmune antigen and not foreign invaders. This review examines inverse vaccination strategies that employ particle-based delivery systems to promote immune tolerance in MS. It highlights how nano- and microparticles have been engineered to deliver myelin-derived autoantigens, with or without immunomodulatory cues, to induce regulatory T cells, suppress effector responses, or target antigen-presenting cells in a tolerogenic manner. Promising delivery platforms including polylactic-<i>co</i>-glycolic acid (PLGA), acetalated dextran, lignin, iron oxide, gold, and liposomal systems are highlighted, with a focus on how their design influences antigen-specific tolerance induction. Key design principles and challenges are outlined to guide the future development of particle-based inverse vaccines for MS.