Integrin αvβ6 can convert the transforming growth factor (TGF)-β precursor to the mature form. Resiquimod (R848) can generate TGF-β-producing regulatory T cells (Treg). Thus, to concurrent administration of specific antigen and R848 may generate antigen-specific Tregs, that is expected to restore immune tolerance in subjects with airway allergic diseases (AAD). A bio-nanoparticle, designated Rexo, containing an antigen/MHC II complex and R848, was naturally assembled in dendritic cells, that was released as an exosome. An AAD mouse model was developed used to test the effects of Rexo on restoring the immune tolerance in the airways. Exposure to R848 failed to induce Tregs in the β6-deficient mouse airway tissues, that were successfully induced in wild type mice. The results were validated inin vitro experiments. R848 activated the TLR7/MyD88/p38 signal pathway to increase the αvβ6 levels in CD4+ T cells, the αvβ6 then converted the TGF-β precursor to its mature form, and thus, induced Treg generation. Administration of Rexo restored the antigen-specific immune tolerance in the airways manifesting efficiently suppressing experimental AAD by inducing antigen-specific Tregs in the airways and inhibiting antigen-specific Th2 response. Rexos can inhibit experimental AAD via inducing antigen-specific Tregs to restore immune tolerance in the airway tissues, suggesting that Rexos have the translational potential to be used in the treatment of AAD. Copyright © 2020. Published by Elsevier B.V.