Liver‐Targeted Tolerogenic Vaccines: A Nano‐Membrane Coupled Approach for Autoimmune Disease Therapies

The co-delivery of auto-antigens and immunomodulators for tolerance induction holds great potential in the treatment of autoimmune diseases. However, their efficacy in enriching antigens within target cells remains limited, and the use of immunomodulators poses a risk for systemic immunosuppression. Here, an apoptotic erythrocyte-derived membrane is developed for the first time, demonstrating its strong abilities to target hepatic antigen-presenting cells (APCs) and stimulate negative regulatory pathways. These apoptotic cell membranes are engineered onto the surface of intravenous lipid emulsions encapsulating disease-associated antigens to generate a tolerogenic vaccine. This nano-membrane coupled structure facilitates robust antigen loading, efficient liver delivery, and uptake by hepatic APCs; while, concurrently downregulating the expression of costimulatory molecules to promote immune tolerance. Intravenous administration of this tolerogenic vaccine induces multiple regulatory cell subpopulations, particularly IL-10 secreting T cells, regulatory B cells, and memory regulatory T cells, collectively conferring effective protection against celiac disease, rheumatoid arthritis, and type 1 diabetes in murine models. More importantly, it is demonstrated that this vaccine induces antigen-specific immune tolerance without compromising the normal immune responses to other antigens. The findings provide solid support for the application of this hepatic APCs-targeted tolerogenic vaccine as a versatile and translatable platform for combating autoimmune diseases.