News & Analysis Capsule Makes RNA-and DNA-Based Drugs Easier to Swallow MIT Researchers/MIT News D iseases ranging from cancer to COVID-19 can be e ec-tively 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) via an ingestible milli-injector capsule. 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 accom-plished through an injectable. “Nucleic acids, in particular RNA, can be extremely sensitive to degradation, particularly in the digestive tract,” said Giovanni Traverso, PhD, assistant professor of Mechanical Engineering at MIT and a gastroenterologist at Brigham and Women’s Hospital. “Overcoming this challenge opens up multiple approaches to therapy, including potential vaccination through the oral route.” Traverso and colleagues recently described their latest work in Matter , in an article titled, “Oral mRNA delivery using capsule-mediated gastrointestinal tissue injections.” The sci-entists showed that their capsule can deliver up to 150 mi-crograms of RNA to the stomach lining in one of their animal models. (The mRNA-based COVID-19 vaccine from Moderna uses about 100 micrograms of RNA, and the P zer vaccine uses just 30 micrograms of RNA.) Traverso is one of the study’s senior authors. The other is Robert Langer, PhD, an MIT professor and a member of MIT’s Koch Institute for Integrative Cancer Research. In earlier studies, the team designed capsules for the oral delivery of drugs such as the peptide hormone insulin and large mol-ecules such as mono-clonal antibodies into the stomach lining. In the current study, the team took extra steps to ensure that mRNA was delivered intact. The researchers synthesized and screened a library of branched hybrid poly (β amino ester) mRNA nanoparticles for transfection e ciency. They then com-bined the best-performing formulations with ingestible capsules that delivered the drug directly into the stomach lining. The researchers rst injected the mRNA nanoparticles into the stomach in mice, demonstrating that RNA that encoded a reporter protein was successfully taken up by cells. Working with scientists at Novo Nordisk , the researchers freeze-dried the RNA-nanoparticle complexes and packaged them into their drug delivery capsules. For pigs, they loaded about 50 micro-grams of mRNA per capsule, and then they deployed three cap-sules, for a total of 150 micrograms of mRNA. Through the por-cine studies, the researchers demonstrated successful delivery of RNA to cells of the stomach, but not to the cells of other organs. The investigators hope to increase RNA uptake in other organs by changing the composition of the nanoparticles or through larger doses. The scientists also believe that it may also be possi-ble to generate a strong immune response with delivery only to the stomach. In future studies, the scientists plan to explore the possibility of generating a systemic immune response by deliver-ing mRNA vaccines via their capsule. 14 | MARCH 2022 | Genetic Engineering & Biotechnology News | GENengnews. com Felice Frankel
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