PROJECT SUMMARY/ABSTRACT Type 1 diabetes (T1D) is an autoimmune disease that affects 1 in 300 people by the age of 18 in the US. T1D is characterized by acute onset of hyperglycemia resulting from immune-mediated destruction of the insulin- producing β-cells in the pancreas. There is currently no cure for T1D and the disease requires constant management where the current standard of care/management is injected or pumped insulin. Thus, there is an urgent need for new and effective treatment options for T1D patients. While self-reactive CD4 and CD8 T cells are central pathogenic drivers, regulatory T cells (Tregs) have been shown to restrain autoimmunity and maintain immune tolerance through multiple mechanisms. In T1D patients, impaired Treg function have been shown to contribute to disease susceptibility. Thus, induction of Tregs holds great promise in correcting the aberrant autoreactive T cell activities and preventing the progression of T1D. However, it remains unknown how to induce Tregs in a safe and effective manner for the potential treatment of T1D. Here, we propose to develop a novel strategy for immunotherapy against T1D. Toward this goal, we have developed synthetic high-density lipoprotein NanoDiscs that are particularly well suited for lymph node targeting. Our preliminary data generated in a murine model of T1D and experimental autoimmune encephalomyelitis have shown that NanoDiscs carrying antigens only induce robust Treg response and achieve immune tolerance. Based on our compelling proof-of-concept data, we propose to develop NanoDiscs carrying antigens to promote antigen-specific immune tolerance against T1D. The proposed research will provide a new strategy for modulating immune microenvironment of pancreas and an avenue for immune tolerance against T1D.