Route‐Gated Lymphatic Delivery of Antigen‐Only Gliadin Nanoparticles for Celiac Disease‐Oriented Immune Modulation

Celiac disease (CeD) lacks approved pharmacologic therapy. Targeted delivery of antigens to immune inductive sites may provide a means to modulate pathogenic immune responses, yet practical delivery remains challenging. We show that minimal, adjuvant-free, self-assembled gliadin nanoparticles (L@GNP) attenuated antibody boosting after exploratory intravenous (i.v.) pre-exposure. Both soluble gliadin and L@GNP attenuated subsequent anti-gliadin antibody boosting under the tested i.v. conditions, with L@GNP providing a particulate antigen format with a controlled surface antigen positive rate. Rather than i.v. dosing, subcutaneous (s.c.) administration of L@GNP preferentially accessed draining lymphoid tissues and exhibited temporally coordinated uptake by multiple antigen-presenting cell (APC) populations, characterized by early CD11b+ myeloid-cell capture, transient B220+ cell involvement, and sustained enrichment in CD11c+ APCs at later time points. In a short-term CeD-like mouse model, L@GNP preserved villus architecture as indicated by higher V/C and reduced intestinal inflammation by lowering Transglutaminase 2 (TGM2) and key cytokines, rebalanced Th1/Th2, and increased Foxp3 expression, whereas a rapamycin-loaded counterpart (R/L@GNP) did not confer additional benefit at matched antigen doses. These data highlight route-gated lymphatic access and antigen-only simplicity as materials design principles for immunomodulatory nanomedicines.