Glycolysis-regulating polyphenol nanoparticles restore immune homeostasis and tolerance in autoimmune multiple sclerosis

Pathogenic autoreactive T cells targeting myelin-derived self-antigens are primary drivers of severe multiple sclerosis (MS) progression. Thus, restoring immune homeostasis between effector T cells (Th1 and Th17) and regulatory T (Treg) cells is a promising strategy to hinder MS progression. In MS, metabolic pathway activities, including glycolysis, are elevated to provide the energy and metabolic intermediates necessary for cell proliferation, activation, and cytokine production. In this study, we introduce a therapeutic vaccine for MS composed of epigallocatechin gallate (EGCG) nanoparticles with glycolysis-regulating capabilities co-loaded with myelin-derived autoantigens and the immunosuppressive agent rapamycin. Our nanovaccine effectively reduces glycolysis in MS-mediated activated immune cells by diminishing GLUT1 expression, leading to the inhibition of Th1 and Th17 cell activation and differentiation while simultaneously inducing antigen-specific Treg cells. Metabolic reprogramming of encephalitogenic T cells through systemic administration of a nanovaccine suppresses central nervous system (CNS)-infiltrated self-reactive CD4⁺ T cells and inflamed antigen-presenting cells, effectively dampening autoimmune disorders in an MS-imitating experimental autoimmune encephalomyelitis (EAE) mouse model in both early and late chronic conditions. These findings suggest that the proposed nanovaccine can provide a versatile platform for treating metabolic disruption-mediated autoimmune diseases, such as rheumatoid arthritis, type 1 diabetes, and systemic lupus erythematosus.