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

作者：Xiaohan Jiang, Min Wang, Ruihan Zou, Min Fu, Wentao Fan, Yao Wang, Yao Wang, Chenguang Dai, Zaman Swapnil, Wanjun Wang, Hao Wu, Kunxin Xie, Li Liu, Yan Wang, Yan Wang, Zhining Fan, Lili Zhao · 发表于：ACS Nano · 年份：2025 · DOI：10.1021/acsnano.4c18354 · 被引用次数：5 · 研究领域：Celiac Disease Research and Management、Galectins and Cancer Biology、Helicobacter pylori-related gastroenterology studies

Celiac disease (CeD), triggered by gliadin exposure, necessitates therapeutic strategies that establish an antigen-specific immune tolerance. This study explores the therapeutic efficacy and mechanism of rapamycin–gliadin composite nanoparticles (PLN-GR) for CeD treatment. In vivo analyses demonstrated the efficient uptake of PLN-GR by antigen-presenting cells (APCs), particularly Kupffer cells and splenic dendritic cells (DCs), driving their tolerogenic phenotypic transformation. In a murine CeD model, PLN-GR administration significantly enhanced gluten tolerance and mitigated intestinal inflammation, as indicated by reduced paw edema and improved histopathological parameters. Mechanistically, PLN-GR induced macrophage metabolic reprogramming from glycolysis to oxidative phosphorylation, concomitant with elevated serum itaconate levels. This metabolic shift potentiated interorgan immunoregulatory crosstalk, expanding PD-L1 + tolerogenic splenic DCs while suppressing pathogenic Th1 cell populations. Bone marrow-derived macrophages (BMDMs) from Acod1 –/– 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–...