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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,8,16]]},"abstract":"<jats:p>Although patients generally prefer oral drug delivery to injections, low permeability of the gastrointestinal tract makes this method impossible for most biomacromolecules. One potential solution is codelivery of macromolecules, including therapeutic proteins or nucleic acids, with intestinal permeation enhancers; however, enhancer use has been limited clinically by modest efficacy and toxicity concerns surrounding long-term administration. Here, we hypothesized that plant-based foods, which are well tolerated by the gastrointestinal tract, may contain compounds that enable oral macromolecular absorption without causing adverse effects. Upon testing more than 100 fruits, vegetables, and herbs, we identified strawberry and its red pigment, pelargonidin, as potent, well-tolerated enhancers of intestinal permeability. In mice, an oral capsule formulation comprising pelargonidin and a 1 U\/kg dose of insulin reduced blood glucose levels for over 4 h, with bioactivity exceeding 100% relative to subcutaneous injection. Effects were reversible within 2 h and associated with actin and tight junction rearrangement. Furthermore, daily dosing of mice with pelargonidin for 1 mo resulted in no detectable side effects, including weight loss, tissue damage, or inflammatory responses. These data suggest that pelargonidin is an exceptionally effective enhancer of oral protein uptake that may be safe for routine pharmaceutical use.<\/jats:p>","DOI":"10.1073\/pnas.2207829119","type":"journal-article","created":{"date-parts":[[2022,8,9]],"date-time":"2022-08-09T13:33:58Z","timestamp":1660052038000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":33,"title":["The strawberry-derived permeation enhancer pelargonidin enables oral protein delivery"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6961-1577","authenticated-orcid":false,"given":"Nicholas G.","family":"Lamson","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA, 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine C.","family":"Fein","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, 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