Enzymatic absorption promoters for non-invasive peptide delivery

Peptide drugs offer considerable potential for treating a diverse range of diseases. Yet, their clinical application is generally restricted to injectable therapies. The main challenge hindering their broader use through globally accessible, patient-friendly, and non-invasive delivery routes such as oral or buccal, lies in their poor ability to cross biological barriers effectively. Here, we demonstrate that enzymes can be harnessed to transiently reduce these barriers and improve absorption. As a proof of concept, we employ a mucin-specific protease (mucinase) and a phospholipase to increase mucus diffusivity and epithelial cell membrane permeability, respectively. In a canine model, we show that enteric capsules containing both enzymes, and the peptide drug desmopressin achieved a relative bioavailability of 155 % compared to the drug alone. Additionally, a buccal patch loaded with phospholipase and semaglutide displayed a 5-fold higher bioavailability and lower variability (71.5 % reduction in the coefficient of variation) compared to the commercially available oral tablet. These results suggest that enzymatic modulation of biological barriers holds promise as a strategy to improve non-invasive delivery of peptides and potentially other macromolecular drugs.