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A groundbreaking study introduces stable inhalable mRNA treatment using nanoparticles that hold up during nebulization, showing significant potential in treating lung diseases without injections.
Many people dislike getting shots for treatments or vaccines, so scientists are exploring ways to develop medicines, like those made from messenger RNA (mRNA), that can be inhaled instead. A new study published today (November 13) in the Journal of the American Chemical Society highlights key progress toward creating inhalable mRNA therapies. Researchers describe their advanced lipid-polymer nanoparticle that can hold mRNA in a stable form for nebulization and deliver it effectively as aerosol droplets to the lungs of mice.
Challenges in mRNA Delivery
mRNA medicines work by encoding proteins that could help treat or prevent various diseases, including those affecting the lungs. However, these proteins are fragile and cannot penetrate cells on their own. To protect and deliver mRNA to lung cells, scientists use lipid nanoparticles—tiny fatty spheres that act like “suitcases,” carrying the mRNA safely to its target.
Yet, early versions of these lipid nanoparticles were unsuitable for inhalable treatments, as they tended to clump together or expand in size when sprayed. Previous efforts to solve this issue involved adding polymers, like polyethylene glycol, to the lipid particles. However, this approach did not provide sufficient stability for effective nebulized delivery.
Innovative Solution With Zwitterionic Polymers
Now, Daniel Anderson, Allen Jiang, Sushil Lathwal, and colleagues have hypothesized that a different type of polymer, one with repeating units of positively and negatively charged components called a zwitterionic polymer, could create mRNA-containing lipid nanoparticles that can withstand nebulization (turning a liquid into a mist).
The researchers synthesized a variety of lipid nanoparticles out of four ingredients: a phospholipid, cholesterol, an ionizable lipid, and lipids of different lengths attached to zwitterionic polymers of various lengths. Initial tests indicated that many of the resulting lipid nanoparticles efficiently held mRNA and didn’t change size during misting or after being misted.
Effective mRNA Delivery in Animal Trials
Then in animal trials, the researchers determined that a lower-cholesterol version of the lipid nanoparticles with zwitterionic polymers was the optimal formulation for aerosol delivery. When transporting an mRNA encoding a luminescent protein, this nanoparticle produced the highest luminescence within the animals’ lungs and a uniform protein expression in the tissues, thereby demonstrating that it had the best ability to deliver inhaled mRNA.
Mice given three airborne doses of the optimal nanoparticle over a 2-week period maintained consistent luminescent protein production without experiencing measurable inflammation in the lungs. The delivery method even worked in mice with a thick layer of mucus lining their airways, which was meant to model the lungs of people with cystic fibrosis.
Taken together, the researchers say this set of results demonstrates the successful airborne delivery of mRNA using zwitterionic polymers in lipid nanoparticles. As a next step, they plan to conduct tests in larger animals.
Reference: “Zwitterionic Polymer-Functionalized Lipid Nanoparticles for the Nebulized Delivery of mRNA” 13 November 2024, Journal of the American Chemical Society.
DOI: 10.1021/jacs.4c11347
The authors acknowledge funding from the U.S. National Institutes of Health, Sanofi (formerly Translate Bio), the Cystic Fibrosis Foundation, the Massachusetts Institute of Technology Undergraduate Research Opportunities Program, and the Koch Institute Support (core) Grant from the National Cancer Institute.
The authors have filed a patent on this technology. Some authors are founders of oRNA Therapeutics and Moderna, biotechnology companies that produce RNA and mRNA medicines, respectively.
