Restoring immunoglobulin A/polymeric immunoglobulin receptor transport axis for the oral treatment of inflammatory bowel disease.

The immunoglobulin A/polymeric immunoglobulin receptor (IgA/pIgR) transport axis orchestrates mucosal immunity, epithelial integrity, and microbiota homeostasis, and its dysregulation promotes the development and progression of inflammatory bowel disease (IBD). However, therapeutic strategies aimed at restoring this axis remain underdeveloped. In this study, we developed an innovative oral therapy utilizing hybrid extracellular vesicles to specifically modulate the IgA/pIgR transport axis for IBD treatment. Our findings demonstrate that this oral targeting strategy effectively upregulates epithelial pIgR expression and increases the transport of dimeric IgA into intestinal lumen, thereby integrating immune regulation, epithelial barrier repair, and microbiota remodeling. This approach successfully treated DSS-induced colitis, restoring multiple disease parameters to levels comparable to those observed in healthy mice. Collectively, this work provides the first evidence for the therapeutic benefit of selectively restoring the IgA/pIgR transport axis in IBD via the oral route.