Epigenetically Reprogrammed Nanovesicles as Inverse Vaccines for Antigen-Specific Immune Tolerance in Autoimmune...

The development of antigen-specific immunotherapy for autoimmune diseases constitutes an important unmet clinical need. Here we present an innovative inverse vaccine platform leveraging epigenetic reprogramming to induce durable antigen-specific immune tolerance. This inverse vaccine (mDCNVreg) is constructed using artificial cell membrane nanovesicles derived from IFN-γ-primed regulatory dendritic cells subjected to epigenetic modulation. The engineered mDCNVreg features upregulated MHC-II expression enabling targeted antigen presentation, suppressed costimulatory molecules expression, and an enhanced coinhibitory molecules display. Through coordinated mechanisms involving enhanced lymphoid trafficking and phenotype stabilization, this platform significantly enhances antigen delivery to secondary lymphoid organs while maintaining tolerogenic potency. Crucially, mDCNVreg directly induces CD4+ T cell clonal anergy through epitope-specific interactions, establishing long-lasting immune tolerance. This work demonstrates a promising epigenetic engineering approach for reverse vaccine design in personalized autoimmune disease therapy.