Wood-Derived Lignin-Based Tolerogenic Nanoparticle Vaccine for Treating Autoimmune Neurodegenerative Disorders

Multiple sclerosis (MS) is an autoimmune neurological disease in which autoreactive CD4⁺ T cells attack the central nervous system (CNS) in response to myelin-derived self-antigens. Immunosuppressive drugs are currently used for the management of MS. However, short-term efficacy and non-antigen specificity are major limitations of these drugs. Thus, the induction of antigen-specific immune tolerance via interaction with tolerogenic antigen-presenting cells (APCs) is proposed for long-term therapeutic efficacy to treat MS. In this study, we propose that lignin, an abundant natural by-product derived from wood and plants, can be utilized as a cost-effective nanovaccine for treating MS. The nanovaccine, consisting of carboxyl-modified lignin nanoparticles (LNPs) conjugated with MS-relevant antigens via an EDC/NHS coupling process, exhibited the potent capacity to induce a tolerogenic phenotype in APCs and antigen-specific Foxp3⁺CD4⁺ T cells. Systemic immunization with self-antigen-carrying LNPs with intrinsic antioxidant properties in a human MS-mimicking experimental autoimmune encephalomyelitis (EAE) mouse model led to the suppression of the infiltration of autoreactive CD4⁺T cells and inflammatory APCs into the CNS, and enhanced remyelination of the CNS, thereby alleviating ongoing MS disease in both early and late chronic stages. Furthermore, incorporating an immunosuppressive drug, such as dexamethasone, into an LNP-based tolerogenic nanovaccine could enhance the recovery of EAE mice during the severe chronic stage. As lignin is the most abundant biomass and waste by-product in the pulping industry, a lignin-based tolerogenic vaccine could serve as an innovative, economical, high-value vaccine platform with potent therapeutic efficacy in treating autoimmune diseases.