Diseases ranging from cancer to COVID can be effectively treated with RNA and DNA- based drugs. Until now, these large and labile life-saving drugs needed to be injected, posing an obstacle to treatment for people with a deathly fear of hypodermic needles.
Scientists at the Massachusetts Institute of Technology (MIT) have now devised a way to deliver nucleic acid-based drugs such as mRNA vaccines, antisense oligonucleotides, and siRNA, in a capsule that can be administered orally. This advancement in the mode of delivery for labile RNA and DNA based therapeutics could increase their receptivity, tolerability, and applicability. Oral delivery has the added advantage of enabling local transfection of cells in the digestive tract, which cannot be easily accomplished through an injectable.
“Nucleic acids, in particular RNA, can be extremely sensitive to degradation particularly in the digestive tract. Overcoming this challenge opens up multiple approaches to therapy, including potential vaccination through the oral route,” said Giovanni Traverso, PhD, assistant professor of Mechanical Engineering at MIT and a gastroenterologist at Brigham and Women’s Hospital.
In the new study published in an article in the journal Matter on Janaury 31, titled “Oral mRNA delivery using capsule-mediated gastrointestinal tissue injections,” Traverso and his team showed that the capsule they developed can deliver up to 150 micrograms of RNA to the stomach in a pig model. The mRNA-based Covid vaccine from Moderna uses about 100 micrograms of RNA and the Pfizer vaccine uses just 30 micrograms of RNA.
Traverso and Robert Langer, PhD, Professor at MIT and a member of MIT’s Koch Institute for Integrative Cancer Research, are the senior authors of the study.
In earlier studies, the team has designed capsules for the oral delivery of solid drugs such as the peptide hormone insulin into the stomach lining and large molecules such as monoclonal antibodies in liquid form.
Nucleic acids are not just large molecules, these are also easily degraded in body fluids, and therefore must be delivered in protective particle to their intended target. To accomplish this, the MIT team synthesized and screened a library of branched hybrid poly (β amino ester) mRNA nanoparticles for transfection efficiency. They then combined the highest performing formulations with ingestible capsules that delivered the drug directly into the stomach lining.
The team’s previous work showed that branched versions of these polymers are more effective than linear polymers at protecting nucleic acids and getting them into cells. They also showed that using two of these polymers together is more effective than just one.
“We made a library of branched, hybrid poly β amino esters and we found that the lead polymers within them would do better than the lead polymers within the linear library,” said Ameya Kirtane, PhD, an MIT postdoctoral researcher and a lead author on the study. “What that allows us to do now is to reduce the total amount of nanoparticles that we are administering.”
The researchers first injected the mRNA nanoparticles into the stomach in mice, demonstrating that the delivered RNA that encoded a reporter protein was successfully taken up by cells. The researchers observed the expression of the reporter protein in the stomachs and liver in mice. This indicated RNA taken up by organs in the body is transported to the liver, the center of metabolic detoxification.
“We validated the performance of formulations and devices in rodents and pigs, demonstrating protein translation in the delta, gastric and parietal cells of the gastric mucosa in addition to systemic uptake,” the authors note.
Working with scientists at Novo Nordisk, a healthcare company headquartered in Denmark, the researchers freeze-dried the RNA-nanoparticle complexes and packaged them into their drug delivery capsules. In pigs, they could deliver about 50 micrograms of mRNA per capsule, and three capsules, resulting in a total delivery of 150 micrograms mRNA. Through the porcine studies, the researchers demonstrated successful delivery of RNA to cells of the stomach but not in other organs.
The investigators hope to increase RNA uptake in other organs by changing the composition of the nanoparticles or through larger doses. Alex Abramson, PhD, also a lead author on the study, said, it may also be possible to generate a strong immune response with delivery only to the stomach.
“There are many immune cells in the gastrointestinal tract. Stimulating the immune system of the gastrointestinal tract is a known way of creating an immune response,” Abramson said. “When you have systemic delivery through intravenous injection or subcutaneous injection, it’s not very easy to target the stomach. We see this as a potential way to treat different diseases that are present in the gastrointestinal tract.”
In future studies, the scientists are exploring the possibility of generating a systemic immune response by delivering mRNA vaccines using their capsule.
