We are working closely with our bioengineer collaborators to investigate the use of poly(lactide-co-glycolide) (PLG) nanostructures for efficient modifications of both innate and adaptive immunity elicited by islet cell transplantation to promote islet engraftment and long-term survival. A two-pronged approach will be used to: (1) modify the local environment of the islet implantation site to minimize non-specific inflammation and enhance local immunoregulation to promote maximal islet survival with a minimal number of islets; (2) modify the systemic immune response directed at the allogeneic and/or xenogeneic islets to induce donor-specific tolerance and promote long-term islet allo/xeno-graft function in the absence of indefinite immunosuppression. The former will be accomplished by fabricating nano-scaffolds with targeted delivery of factors and cell populations. The latter will be accomplished by fabricating nano-particles as carriers of donor antigens that will specifically target host cellular machineries and trigger downstream tolerogenic pathways including deletion, anergy and regulation. Our ultimate goal is to design biomaterials-based, cell-free strategies for inducing long-term donor-specific protection and promoting long-term glycemic controls with a minimal islet cell transplant mass in diabetic recipients.