Construction and Evaluation of Liraglutide Delivery System based on Milk Exosomes: A New Idea for Oral Peptide Delivery

Background: Increasing the bioavailability of peptide or protein drugs have always been an important topic in the field of pharmacy. Milk exosomes as a carrier for oral drug delivery systems have begun to attract attention in recent years. The application of oral milk exosomes carriers to peptide drugs, such as liraglutide, is worth trying. Objectives: Milk-derived exosomes are used in this study to try to encapsulate the GLP-1 receptor agonist liraglutide and the feasibility of using this drug delivery system for oral biomolecules delivery in the future is explored. Methods: The size and morphology of milk exosomes were characterized. The gastrointestinal stability of milk exosomes was evaluated in a dialysis bag. The cellular uptake of milk exosomes in the intestinal cells was observed. Six drug loading methods have been evaluated and compared preliminarily and they are incubation method, sonication method, extrusion method, freeze-thaw cycles method, saponin-assisted method and electroporation method. Results: As demonstrated in this study, milk exosomes showed significant stability in the gastrointestinal environment and excellent affinity with intestinal cells, indicating their unique benefits used for drug oral delivery. Effective drug loading method for exosomes is challenging. Among the six drug loading methods used in this study, the liraglutide-Exo prepared by the extrusion method obtained the largest drug load, which was 2.45 times the direct incubation method. The liraglutide-Exo obtained by the freeze-thaw cycles method has the smallest morphological change. Conclusion: The study showed that milk exosome-based oral drug delivery systems are promising.