No one likes getting a needle but most want a vaccine. A new paper shows progress for messenger RNA (mRNA), that can be sprayed and inhaled thanks to improved lipid-polymer nanoparticle technology for holding mRNA that is stable when nebulized and successfully delivers aerosols, liquid droplets, in mouse lungs. 

A mouse study means this is only EXPLORATORY but the authors of the paper, including scientists from oRNA Therapeutics (RNA medicine) and Moderna (mRNA medicine), have filed for a patent while they get ready to see about human trials. 

The benefit to mRNA medicines is the ability encode proteins that could treat or prevent a variety of illnesses but such proteins are fragile and can’t enter cells by themselves. To get them inside lung cells,  lipid nanoparticles, basically tiny balls of fat are good shipping containers but those don't work for inhalable medications because the nanoparticles clump together or increase in size when sprayed into the air.



To improve that, some attached polymers like polyethylene glyco the particle’s fatty components, but it still wasn't stable enough. The recent study hypothesized that repeating units of positively and negatively charged components called a zwitterionic polymer could create mRNA-containing lipid nanoparticles that can withstand turning a liquid into a mist. 

They synthesized lipid nanoparticles out of 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. In animal tests, 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 and if that works, on to humans.