Most individuals tend to dislike receiving injections for treatments or vaccinations. In response, researchers are aiming to develop medicines, like messenger RNA (mRNA), that can be administered through spraying and inhalation. A recent study published in the Journal of the American Chemical Society discusses advancements towards the feasibility of inhalable mRNA therapies. The researchers describe their enhanced lipid-polymer nanoparticles designed to encapsulate mRNA, which remain stable when aerosolized and effectively deliver liquid droplets to the lungs of mice.
Most individuals tend to dislike receiving injections for treatments or vaccinations. In response, researchers are aiming to develop medicines, like messenger RNA (mRNA), that can be administered through spraying and inhalation. A recent study published in the Journal of the American Chemical Society discusses advancements towards the feasibility of inhalable mRNA therapies. The researchers describe their enhanced lipid-polymer nanoparticles designed to encapsulate mRNA, which remain stable when aerosolized and effectively deliver liquid droplets to the lungs of mice.
mRNA treatments are designed to encode proteins that can help prevent or treat a range of diseases, including respiratory conditions. However, since these proteins are fragile, they cannot penetrate cells independently. To deliver mRNA into lung cells, researchers use tiny lipid nanoparticles that act like small containers, safeguarding and transporting the mRNA until it reaches its target. Earlier types of these lipid nanoparticles weren’t effective for inhalable treatments, as they would clump or expand when aerosolized. Previous attempts to tackle this involved adding polymers, such as polyethylene glycol, to one of the lipid components, but this did not sufficiently stabilize the lipid nanoparticles.
In this study, Daniel Anderson, Allen Jiang, Sushil Lathwal, and their team proposed that a different kind of polymer, known as zwitterionic polymer—which features alternating positive and negative charged units—could create more stable mRNA-loaded lipid nanoparticles that maintain their structure during nebulization (the process of converting liquid into mist). They synthesized various lipid nanoparticles using four components: a phospholipid, cholesterol, an ionizable lipid, and lipids of varying lengths bound to zwitterionic polymers of different lengths. Early tests showed that many of these nanoparticles managed to successfully hold mRNA without changing size during misting or afterward.
In subsequent animal tests, the researchers found that a lower-cholesterol variant of the lipid nanoparticles with zwitterionic polymers provided the best results for aerosol delivery. When delivering an mRNA that coded for a luminescent protein, this particular nanoparticle exhibited the highest levels of luminescence in the subjects’ lungs and uniform protein expression throughout the tissues, indicating effective delivery of the inhaled mRNA. Mice that received three doses of the optimal nanoparticle over a two-week span showed ongoing luminescent protein production without noticeable lung inflammation. Additionally, this delivery method proved effective even in mice with a thick mucus layer in their airways, designed to simulate the lungs of individuals with cystic fibrosis. Collectively, the researchers assert that these findings illustrate the successful delivery of mRNA through the air using zwitterionic polymers in lipid nanoparticles. As a next step, tests in larger animals are planned.
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 for this technology. Some authors are co-founders of oRNA Therapeutics and Moderna, biotech companies specializing in RNA and mRNA therapies, respectively.
