From stem cells to nanomedicine: A multimodal approach targeting pancreatic fibrosis via MFGE8-dependent ANXA1-SMAD2/3 axis.

Chronic pancreatitis (CP) is a progressive fibrotic inflammation syndrome that leads to pancreatic insufficiency, for which there is a paucity of effective therapeutic options. Owing to their multidirectional differentiation potential and immunomodulatory capabilities, mesenchymal stem cells (MSCs) hold promise for the amelioration of chronic diseases. In this study, we demonstrated for the first time that umbilical cord-derived MSCs (UCMSCs) and their extracellular vesicles (UCMSC-EVs) mitigated pancreatic acinar cell injury, reduced macrophage infiltration, and alleviated pancreatic fibrosis in a murine model of chronic pancreatitis. Furthermore, we comprehensively elucidated the intricate regulatory effects of UCMSC-EVs on fibrotic signaling pathways in pancreatic stellate cells. Mechanistically, EVs secreted by UCMSCs modulated the ANXA1-SMAD2/3 signaling axis in pancreatic stellate cells via the release of milk fat globule-EGF factor 8 (MFGE8), leading to the inhibition of fibrotic gene expression. Additionally, we developed a novel drug delivery platform named rhMFGE8 NPs, which exhibited marked antifibrotic efficacy and an outstanding biosafety profile. This investigation highlights the therapeutic potential of UCMSCs, UCMSC-EVs, and rhMFGE8 NPs for CP treatment, providing a foundation for the development of innovative antifibrotic therapies.