Modulating the elasticity of milk exosome-based hybrid vesicles to optimize transepithelial transport and enhance oral peptide delivery.

To address challenges such as limited loading capacity, restricted targeting precision, and low yield of natural exosomes as drug carriers, the fusion of liposomes and exosomes to create hybrid vesicles has emerged as a viable solution approach. While current research mainly focuses on designing functionalized liposomes, less attention is given to how liposome membrane materials affect the elasticity of these hybrids and their delivery efficiency. This study utilized milk exosomes (mExos) as model exosomes, and generated hybrid vesicles with varying elasticity through the fusion of phospholipids with differing chain lengths, examining the disparities among various hybrid vesicles in their ability to overcoming the gastrointestinal barriers. It was observed that while hard hybrid vesicles exhibited reduced mucus penetration compared to soft hybrid vesicles, they demonstrated a notably higher efficacy in traversing the epithelial cell barrier. The enhanced transepithelial cell capability of hard vesicles can be attributed to their reduced tendency to aggregate in the lysosome through the down-regulated clathrin-mediated endocytosis pathway, as well as by the strengthening of the endoplasmic reticulum-Golgi exocytosis pathway due to their rigid characteristics. In comparison to soft hybrid vesicles, semaglutide (SET) loaded hard hybrid vesicles demonstrated improved in vivo epithelial permeability, enhanced oral bioavailability, and better therapeutic effectiveness. This study could provide valuable insights for determining the optimal elasticity of exosome-liposome hybrid vesicles in the development of oral nanocarriers.