ABSTRACT Currently no cure exists for the autoimmune disease Type 1 diabetes (T1D). The Juvenile Diabetes Research Foundation estimates ~80 individuals are newly diagnosed with the disease, daily. Due to immune-mediated destruction of the insulin-producing β cells, current treatment of T1D is limited to daily exogenous insulin administration. What is needed are immunotherapies that selectively suppress cell autoimmunity for the prevention and treatment of T1D. One approach is the administration of cell autoantigen to suppress and tolerize diabetogenic effector T cells. Importantly, this approach avoids effects on protective immunity seen with other T1D immunotherapies tested in the clinic. Although promising, antigen-based immunotherapy for T1D has shown only modest clinical results. We have been studying biodegradable, acetalated dextran microparticles (Ac-DEX MPs) as a polymeric vehicle to deliver antigen and immunomodulatory drugs. Ac-DEX MPs have a number of properties well suited for suppressing T cell-mediated autoimmunity and reestablishing self-tolerance. Notably, Ac-DEX MPs can be manipulated to release cargo in vivo in a tunable manner. We have shown that timing of cargo release has marked effects on the nature and magnitude of the immune response that is elicited. Furthermore, using this platform, we have recently shown that delivery of Ac-DEX MPs encapsulating a tolerizing agent (rapamycin) and a cell-derived peptide effectively prevents diabetes in an adoptive T cell transfer model of T1D. Accordingly, the focus of the current proposal is to develop and characterize the tolerogenic properties of Ac-DEX MPs encapsulating immunomodulatory drugs and cell-derived peptides as a means to selectively suppress the diabetogenic response. We hypothesize that the rate of MP degradation plus the co-encapsulation of immunomodulatory agent enhances the tolerogenic potency of our peptide-based vaccine. To test this hypothesis, we have proposed two Aims: Specific Aim 1: Encapsulation of rapamycin and antigens in tunable Ac-DEX particles and optimization of particle system. Here we will establish drug, dosing, and degradation rate of the microparticles for optimum inhibition of the autoimmune response. Specific Aim 2: Evaluation of Ac-DEX particle formulation and mechanism of tolerance in animal models of T1D. In this Aim, we will evaluate the trafficking of the MPs as related to immune cell uptake, characterizing the underlying tolerogenic responses generated by the formulation, evaluate the protective and therapeutic efficacy of the platform, and confirm that the therapy has no effect on acquired immunity.