From vaccines to gene therapies, mRNA medicines often rely on tiny fat-based particles called lipid nanoparticles, or LNPs, to carry treatments where they need to go. But researchers still face a fundamental challenge: getting those therapies to the organs where they are needed most while limiting side effects elsewhere in the body.

Now, researchers at Georgia Tech and Emory University have discovered that delivering LNP medicines directly to various areas of the gastrointestinal (GI) tract — from the cheeks to the stomach to the rectum — could alter where the therapies travel in the body after being absorbed. This enables more precise targeting and opens new possibilities for mRNA therapies and vaccines.

Several technologies are currently in development that enable oral and GI nucleic acid delivery, including pills, patches, and endoscopic injections. 

"Here we show that oral delivery of mRNA wouldn’t just enhance the patient experience compared to injections, but it also may enable improved or even completely new treatments," said Alex Abramson, an assistant professor in the School of Chemical and Biomolecular Engineering (ChBE).

"We're able to deliver to organs that are hard to target via traditional administration methods while simultaneously reducing uptake in organs normally associated with toxicity."

The researchers published their findings in ACS Nano in September.

Delivery Direction

Typically, LNPs are delivered subcutaneously or intravenously, but that can mean the drugs affect more than just the intended target. Drug interactions with organs such as the liver, lungs, and spleen can cause unwanted side effects that limit how much medicine can be administered. The researchers found that delivering LNPs to different regions of the GI tract changed where the nanoparticles traveled in the body, allowing them to reach targets like the pancreas and lymph nodes while reducing targeting to the liver, lungs, and spleen. 

"We found that the LNP was completely safe at a very high dose when delivered via a gastric route of administration," said Abdulraouf Abbas, a Ph.D. student in James Dahlman's Emory lab. Dahlman is a McCamish Early Career Professor in the Department of Biomedical Engineering at Georgia Tech and Emory School of Medicine.

"What's really exciting about not affecting the liver and the lungs is that it may allow us to increase the dose without increasing the side effects," Abramson said.

Even better, if the goal is vaccination, the dose could be smaller because the therapy is delivered more directly to the desired target. "Not only are we potentially improving LNP benefits by changing how it is administered, but we could even potentially decrease the cost of those mRNA vaccines or mRNA drugs," said Ramy Ghanim, a ChBE Ph.D. student.

Different Routes, Different Results

Using mouse models, the researchers mapped where nanoparticles traveled after microneedle injections delivered them to different parts of the GI tract. Once they identified which organs received the therapy, they could begin exploring potential medical applications. 

"If you're designing mRNA for a vaccine, then you want to prioritize targeting the lymph nodes. We saw in that case that delivering to the cheek matched or improved the immune response of a vaccine compared to a traditional injection," Ghanim said. "But just because that route is optimal for that application doesn't mean one solution fits all applications."

For example, delivery through the stomach was particularly useful for targeting the pancreas. The researchers also showed that delivering glucagon-like peptide-1 (GLP-1) mRNA doses through the stomach improved blood sugar regulation in mouse models. GLP-1 medications are potent treatments used to treat obesity and diabetes.

The researchers hope to test more disease models in the future and eventually bring this technology into the clinic to help patients.

This work was funded in part by: The Georgia Research Alliance and Georgia Clinical & Translational Science Alliance’s 2023 Regenerative Engineering Medicine pilot grant co-awarded to Dahlman and Abramson labs, Lakshmi and Subramonian Shankar Fellowship and Diabetes Translational Accelerator, a National Science Foundation Graduate Research Fellowship Program, National Institutes of Health Maximizing Investigators' Research Award grant R35GM150689, and the National Research Foundation of Korea.

CITATION: Abdulraouf M. Abbas, Ramy Ghanim, Sebastian Rudden, David Schultz, Bora Jang, Avraham Shakked, Hyejin Kim, James E. Dahlman, Alex Abramson; Targeted Gastrointestinal Delivery of mRNA Lipid Nanoparticles Enables Systemic Vaccination and Glucagon-like Peptide-1 Metabolic Therapy. ACS Nano 2026; https://doi.org/10.1021/acsnano.5c18549