Subcutaneous nanotherapy for islet transplantation preserves functional protective immunity in a staphylococcus aureus skin infection model 2717

Abstract Description The approval of Lantidra, the first cellular therapy for type 1 diabetes, is a milestone for islet transplantation (TX), offering an alternative to insulin therapy. However, TX adoption is constrained by the need for systemic immunosuppression, which heightens nosocomial infection risks, including Methicillin-resistant Staphylococcus aureus (MRSA) skin infection, leading to increased TX failure and mortality. Antigen-specific tolerance is essential to sustain graft survival while maintaining protective immunity. Nanoscale drug delivery systems, such as those in COVID vaccines, demonstrate promise in modulating immune responses. We have developed polymeric nanoparticle vesicles (polymersomes) that enhance the tolerogenic effects of encapsulated therapeutics. In a murine model, subcutaneous injections of rapamycin-loaded polymersomes (rPS) in an optimized two-week regimen preserved 83% of fully mismatched islet grafts and sustained normoglycemia for 100+ days. In an MRSA infection model, rPS supported weight recovery (p < 0.0001) and rapid wound closure (p < 0.05). Unlike rPS, standard rapamycin resulted in systemic infection, indicated by elevated hepatic bacterial burden (p < 0.01). Despite rPS uptake by antigen presenting cells, rPS-treated mice showed elevated IL-6 levels compared to untreated controls (p < 0.05), suggesting cytokine production was not suppressed. Future studies will examine the interplay between acute infection and TX tolerance induction. Funding Sources Strategic Research Agreement (3-SRA-2023-1389-S-B) with BreakthroughT1D. Topic Categories Transplantation Immunology (TRAN)