Abstract

Acute pancreatitis (AP)-induced intestinal barrier disruption drives fatal systemic complications. We engineered human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUC-MSC-EVs) to deliver emodin—a bioactive compound limited by poor bioavailability—for targeted intestinal protection. In TNF-α-stimulated intestinal epithelial cells (CCD-841CON), EV-loaded emodin (EVs-Emodin) synergistically suppressed NLRP3 inflammasome activation, pyroptosis, reactive oxygen species production, and inflammatory cytokines, outperforming monotherapies. EVs-Emodin restored cell viability and curtailed apoptosis. In taurocholate-induced AP mice, intravenous EVs-Emodin attenuated systemic inflammation, promoted the expression of Occludin and ZO-1, mitigated intestinal tissue lesions, promoted epithelial regeneration, inhibited inflammasome activation, and alleviated mitochondrial damage. hUC-MSC-EVs overcome emodin's delivery limitations, providing a synergistic strategy to protect the intestinal barrier via NLRP3/pyroptosis inhibition and oxidative stress mitigation, offering a promising therapeutic approach for AP-associated intestinal injury.