Biomedical engineers at Duke University have developed a new approach to delivering GLP-1 medications orally that does not require fasting and maintains their efficacy. The technique could also be useful for any pharmaceutical based on peptides such as insulin or treatments for irritable bowel syndrome, HIV and osteoporosis.
The research appeared online May 13 in the journal Cell Biomaterials.
Peptides are essentially strings of amino acids too short to form proteins. The human body naturally produces at least 7,000 of them that carry out a wide range of functions like healing, hormone regulation and muscle growth. There are dozens of FDA-approved peptide-based medications, including insulin for diabetes and the increasingly popular GLP-1 drugs like Ozempic and Wegovy for weight loss.
Regardless of their use, all peptide drugs have one thing in common: They are typically injected rather than consumed. This is because the stomach's digestive process breaks down peptides the same way it does a chicken breast.
"Over one in eight people in America have already taken a GLP-1, and a significant portion of them are scared of needles," said Max Ney, a postdoctoral researcher at ETH Zurich, who worked on the study as a doctoral student at Duke. "There's been a push for an oral formulation, and our lab is a leading group that works with a biomaterial that we thought could work as a delivery vehicle."
One option already in use combines the peptide with a base to temporarily neutralize stomach acid. This is how current oral GLP-1 formulations work. This approach, however, requires the patient to take the medication on an empty stomach and reduces its effectiveness.
The biomaterial Ney wanted to pursue instead is called an elastin-like polypeptide, or ELP for short. These are also naturally produced by the body and, like proteins, are responsible for regulating many biological processes. But unlike proteins, which have defined shapes, ELPs are more like chaotic globs of noodles that stick together.
That chaos helps researchers tailor the properties of synthetic versions of ELPs. By carefully controlling their amino acid building blocks, biomedical engineers can dictate their structural integrity based on the surrounding environment. This allows researchers to design ELPs that transform between solids and liquids and back again based on variables like acidity and temperature.
"My lab has been working to figure out how to tailor bespoke ELPs for a wide range of applications for over a decade," said Ashutosh Chilkoti, the Alan L. Kaganov Distinguished Professor of Biomedical Engineering. "Drug delivery has long been one of our primary targets, and this use case is particularly well suited to our platform."
To engineer this new delivery system, Ney turned to lowly yeast. When stressed, the internal pH levels of yeast cells often become more acidic, damaging or destroying proteins within. Some yeast, however, have evolved defense mechanisms where polypeptides self-assemble to protect critical components.
Working from this natural example, Ney designed a synthetic version of this self-assembling protection that is sensitive to both temperature and acidity. He then modified a GLP-1 drug to contain the same self-assembling instructions borrowed from the yeast.
When all of the ingredients are put together under the right conditions, the result is a protective bioparticle containing GLP-1 that can be suspended in liquid. When entering the digestive tract, the bioparticles remain solid until they enter the intestines. There, the specific temperatures and pH levels cause them to break down and release the medication, completely bypassing the stomach's destructive acids.
When tested in mice, the new delivery formulation was just as effective at reducing their weight amidst high-calorie diet options as the injected version of the GLP-1. And because all of the constituent parts are easily produced by E. coli, the approach would be easy to scale up for manufacturing purposes.
While pharmaceutical companies do have small molecule oral versions of GLP-1s that can be taken at any time already in clinical trials, early results show a reduced efficacy. And the researchers in this study envision a much wider array of potential uses than only GLP-1s.
"There are a lot of peptide drugs out there that have barriers to development and commercialization that could potentially benefit from this type of a delivery strategy," said Ney. "If people have the option between an injection and an oral medication, they're going to choose the oral. This could also help a lot of peptide drugs become more widely accessible."
The research was supported by the Air Force Office of Scientific Research (FA9550-20-1-0241).
"Intrinsically disordered protein coating for oral delivery of peptide drugs." Max Ney, Parul Sirohi, Yulia Shmidov, Anurag Singh, Gable Wadsworth, Xinghai Li, James Zheng, Erica Peng, Lixin Fan, Tharun Selvam Mahendran, Sonal Deshpande, Navya Tripathi, Jonathan C. Su, Joshua James Milligan, Yun-Xing Wang, Priya R. Banerjee, and Ashutosh Chilkoti. Cell Biomaterials, 2026. DOI: 10.1016/j.celbio.2026.100460
