Harnessing Kupffer Cell Metabolic Rewiring: Rapamycin–Gliadin Nanoparticle as a Pivotal Strategy for Immune Tolerance in Celiac Disease

mice (deficient in itaconate synthesis) failed to induce DC tolerance upon PLN-GR treatment. However, supplementation with the itaconate derivative 4-octyl itaconate (4-OI) restored PD-L1 expression in DC2.4 cells in vitro, revealing that itaconate induces and stabilizes the tolerant DC phenotype. These findings underscore PLN-GR as a novel nanotherapeutic platform for CeD, achieving gliadin-specific tolerance through hepatic-splenic immunometabolic reprogramming and itaconate-dependent PD-L1 regulation, thereby offering a translatable strategy for autoimmune disease management.