Here we seek to understand the structure-based design rules that govern the lymph node targeting at the molecular level to design vaccines against autoimmune diseases. Vaccine approaches to restore antigen- specific immune tolerance to pancreatic beta-cell antigens without global immune suppression are potential therapeutic interventions for Type 1 diabetes (T1D). However, a method for realizing both efficacy and safety is yet to be developed. A major challenge in the development of effective vaccines is efficient delivery of vaccine components to antigen presenting cells (APCs) in lymphoid organs, where the orchestrations of immune cells are initiated. We propose to translate a novel "albumin-hitchhiking" approach to target lymph node to molecular T1D vaccines, via the synthesis of amphiphiles that comprised of an antigen and immunosuppressant linked to lipophilic albumin-binding tail by a solubility-promoting polar polymer chain. Structurally optimized molecular vaccines will be engineered with a lipophilic albumin-binding tail and follow subcutaneous injection, can accumulate in LN via in situ complexation and transport with endogenous albumin. Albumin-hitchhiking approach can simultaneously enhance the efficacy and safety of molecular vaccines via localized vaccine delivery and modulate the antigen presenting cells within lymph node microenvironments, and can be readily translate to clinic.
A significant barrier to autoimmune therapies, particularly novel approaches such as vaccines and immunotherapy, is lack of method to delivery therapeutics to lymph nodes. In this proposal we present a structure-based albumin-hitchhiking approach for local, sustained delivery of autoantigen and tolerogenic adjuvant to lymph node, where they are efficiently filtered by phagocytes and accumulate, promoting peripheral tolerance. This strategy integrates engineering principles in biomaterials and the targeting of immunomodulatory pathways with a novel role in autoimmunity. The results of these studies will have the potential to catalyze the development of next generation of vaccines against autoimmune diseases.