Nanotherapy-mediated biased antigen-presenting cell reprogramming supports T cell anergy to prevent type 1 diabetes

Engineering immune tolerance using endogenously expressed autoantigens could enable early intervention in autoimmune disease. Present therapies suppress T cells to slow disease progression. Here, we develop rapamycin-loaded poly(ethylene glycol)- b -poly(propylene sulfide) polymersomes (rPS) to modulate antigen-presenting cells (APCs) during disease-associated antigen presentation. The rPS morphology enables lymphatic drainage following subcutaneous administration to access APCs in draining lymph nodes. Treatment reduced APC costimulatory marker coexpression and shifted CD4⁺ T cells toward an FR4 ^hi CD73 ^hi anergic phenotype. In a type 1 diabetes (T1D) nonobese diabetic (NOD) mouse model, rPS significantly delayed disease onset relative to the standard of care and selectively prevented hyperglycemia. Mediation via APCs, rPS avoids adverse effects including transient lymphopenia. These findings demonstrate how biomaterial-directed drug delivery can reshape APC-T cell interactions, supporting an antigen-agnostic strategy for delaying autoimmune diabetes without systemic lymphocyte depletion.

Type 1 diabetes (T1D) results from a complex autoimmune attack on insulin-producing pancreatic β cells. While the detection of islet autoantibodies before T1D onset enables the development of early intervention strategies, the temporal dynamics of islet antigen presentation and the full repertoire of relevant islet antigens remain unclear. Current immunotherapies primarily target T cells to halt islet injury but can cause transient systemic immune suppression and are not curative. Herein, we identify a potential new therapeutic strategy by which antigen-presenting cells (APCs) are reprogrammed to arrest T1D progression without systemic lymphodepletion. To this end, we utilize rapamycin-loaded polymersome (rPS) nanocarriers which selectively deliver the rapamycin payload to APCs. When given prior to disease onset, rPS treatment delays and prevents hyperglycemia in comparison to a T cell-directed, antibody-mediated systemic therapy.Importantly, our study provides a comprehensive evaluation of therapeutic intervention and disease progression. Through subcutaneous injection, the nanotherapeutic approach leverages lymphatic drainage to reach the draining lymph nodes. Here, rPS-induced costimulation-deficient APCs can prevent T cell activation without supplying a specific antigen in prediabetic mice. Complex immunoprofiling validated APC reprogramming in vivo and characterized T cell activation state in presymptomatic mice. Overall, this novel biomaterial-mediated approach demonstrates the importance of designing early intervention therapies to disrupt the T cell activation pathway and offer protection to functional β cells and an opportunity to achieve long-term insulin independence.

Rapamycin-loaded polymersomes (rPS) are an APC-directed nanotherapy to slow T1D progressionA short course of subcutaneous (SC) rPS therapy delays T1D onset in early prediabetic miceAPC-mediated reprogramming halts T1D progression without lymphodepletionMaintenance of effector-memory CD4+ T cell anergy is critical to prevent hyperglycemia.