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 FR4hi CD73hi 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.