Few drugs have gained mainstream recognition as quickly or dramatically as glucagon-like peptide-1, a GLP-1 receptor agonist. Originally approved by the FDA to treat type 2 diabetes, it has since also transformed the treatment landscape for obesity and weight management.
These drugs are clearly effective. They stimulate the release of insulin and inhibit the release of another hormone, glucagon, which helps control blood sugar levels. It also helps with weight loss by decreasing appetite and slowing gastric emptying. However, hurdles to widespread use remain, including manufacturing costs, delivery systems, and side effects, especially in low- and middle-income countries.
To address these hurdles, a new study led by Henry Daniel of the School of Dentistry is investigating a new approach to the oral delivery of exenatide and lixisenatide, two GLP-1 receptor agonists previously approved in injectable form by the FDA. The result is Plant Biotechnology Journalshow that lettuce chloroplasts can produce functional GLP-1 peptides, paving the way for more affordable and well-tolerated oral drugs for diabetes and obesity.
No one wants to get an injection even once a week. They want the pills. ”
Daniel, Professor WD Miller, Department of Basic and Translational Sciences, School of Dentistry
However, oral delivery of peptides is complicated by both digestion in the stomach and reduced absorption in the intestine, he explains. And overcoming these hurdles using traditional approaches has been difficult. For example, the recently approved oral formulation of semaglutide (the active ingredient in Ozempic®) requires patients to follow specific fasting and timing instructions (fast, 4 ounces of water, wait 30 minutes) to be effective, and side effects such as nausea, vomiting, and diarrhea remain common.
Building on their pioneering work using plant encapsulation as a delivery method, Daniel and his team genetically engineered lettuce chloroplasts to express exenatide and lixisenatide, thereby protecting the peptides from degradation in the stomach and promoting absorption in the intestine.
“We eat plant cells all the time,” says Daniel. “And we purposefully chose exenatide and lixisenatide because they are used very successfully in the clinic and have a long safety record.”
Incorporating these GLP-1 therapies into the lettuce genome also avoids the synthetic challenges faced by oral formulations, such as the need to adjust the pH of stomach acid to slightly acidic to prevent degradation, he explains.
“Human enzymes cannot digest plant cells,” says Daniel. “But when the plant cell goes to the intestine, bacteria release enzymes that break down the cell wall.”
Their approach also avoids a step in the production of traditional GLP-1 receptor agonists: post-translational modifications required to make the peptide functional, or chemical changes made to the peptide after synthesis.
“For us, chloroplasts do this naturally,” says Daniel. “Plant cells routinely make these modifications, so systems already exist to make these peptides work.”
This delivery platform also allows the use of natural versions of these peptides, which could reduce the risk of side effects, he notes. Current GLP-1 drugs incorporate two types of artificial amino acids to increase their duration in the body.
“Gastrointestinal problems are most likely related to synthetic GLP,” Daniel says. “For the past 45 years, such symptoms have not occurred frequently with natural GLP-1RAs such as lixisenatide and exenatide.”
Finally, reducing the manufacturing steps for GLP-1 receptor agonists also means lowering overall costs. “Because our approach is simple, our costs are different. How much can we charge for lettuce leaves?” Daniel says.
Daniel and his team are now focused on leveraging their experience in preparing kilograms of oral insulin to prepare larger batches of plant-encapsulated GLP-1 receptor agonists.
“We learned how to scale up our preparation here at Penn,” he says. “We are equipped to conduct early-stage clinical trials.”
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university of pennsylvania
Reference magazines:
Shin, R., Daniel, H. (2026). Engineering a marker-free lettuce chloroplast genome to express the functional glucagon-like peptide-1 receptor agonists exenatide and lixisenatide. Plant Biotechnology Journal. DOI: 10.1111/pbi.70554. https://onlinelibrary.wiley.com/doi/10.1111/pbi.70554
