MSC‐Derived Exosomes Alleviate Intestinal Barrier Injury in an IBD‐on‐a‐Chip

ABSTRACT Inflammatory bowel disease (IBD) is a chronic, nonspecific inflammatory condition affecting the colon or gastrointestinal tract, with an unknown etiology. Given the unclear pathogenesis, the development of preclinical models becomes particularly crucial for reflecting its pathological features and supporting effective therapies. In this study, we developed a pumpless IBD‐on‐a‐chip model that allows to replicate the key pathological changes of IBD, including intestinal barrier disruption, intestinal villus destruction, macrophage polarization, inflammatory response, and vascular endothelial detachment. This model was utilized to evaluate the therapeutic effects of 5‐Amino Salicylic Acid (5‐ASA) and mesenchymal stem cell (MSC)‐derived exosomes (MSC‐Exos). The results demonstrated that both 5‐ASA and MSC‐Exos could relieve intestinal damage by protecting the villous structure. Additionally, we discovered that MSC‐Exos could suppress inflammatory responses on the chip by inducing macrophage differentiation toward the M2 phenotype, while transcriptomic analysis revealed both activation and inhibition of specific inflammation‐related pathways. This study presents the first application of an IBD‐on‐a‐chip model to evaluate the therapeutic efficacy of MSC‐Exos, highlighting its potential for advancing new therapeutic strategies for this debilitating disease.