Oral Delivery of Semaglutide and Tirzepatide Using Milk‐Derived Small Extracellular Vesicles

ABSTRACT Therapeutic proteins and peptides have revolutionized modern biomedicine, but their oral delivery is limited by gastrointestinal degradation and barriers. Small extracellular vesicles (sEVs), which are resistant to biochemical degradation and capable of traversing mucus and cellular barriers, hold great promise as next‐generation oral delivery vehicles. Oral semaglutide, the first approved oral GLP‐1 receptor agonist (GLP‐1RA), employs vesicle‐mediated transcellular transport, highlighting the potential of sEVs as an effective delivery vehicle. In this study, we demonstrate the successful oral delivery of two GLP‐1RAs, semaglutide and previously unexplored tirzepatide, using milk‐derived sEVs. Both peptides were efficiently loaded onto sEVs in vitro, and their oral administration effectively reduced blood glucose levels in diabetic db/db mice. Compared with the current SNAC technology, which is limited exclusively to semaglutide, our sEV platform provides broader applicability and versatility for oral peptide drug delivery.