BEIJING, April 4 (Science and Technology Daily) -- U.S. engineers have designed a new type of nanoparticle that can be used in the lungs, where it can deliver messenger RNA (mRNA) encoding useful proteins. With further development, these particles can provide inhalable treatments for cystic fibrosis and other lung diseases. The study was published March 2 in Nature Biotechnology.
Daniel Anderson, a professor in MIT's Department of Chemical Engineering, said this is the first time RNA has been demonstrated for efficient delivery in mouse lungs. Researchers hope it could be used to treat or repair a range of genetic diseases, including cystic fibrosis.
In a study of mice, Anderson and colleagues used these particles to deliver mRNA encoding CRISPR/Cas9 components, which could open the door to designing therapeutic nanoparticles that can cut out and replace disease-causing genes.
In the new study, the researchers set out to develop lipid nanoparticles that could target the lungs. These particles consist of two parts of the molecule: a positively charged head base and a long lipid tail. The positive charge of the head base helps the particle interact with the negatively charged mRNA, and also helps the mRNA escape from cellular structures that can engulf the particle.
At the same time, the lipid tail structure facilitates the passage of particles through the cell membrane. The researchers came up with 10 different chemical structures for the lipid tail, as well as 72 different head groups. By screening different combinations of these structures in mouse experiments, the researchers were able to identify the structures most likely to reach the lungs.
Studies have shown that these particles can be used to transmit mRNA encoding CRISPR/Cas9 components, which are designed to cut off the stop signal genetically encoded into animal lung cells. When the stop signal is removed, the gene for the fluorescent protein is turned on. Measuring this fluorescence signal allowed the researchers to determine the percentage of cells that successfully expressed mRNA.
The researchers found that after one dose of mRNA, about 40 percent of lung epithelial cells were transfected, with two doses bringing levels above 50 percent and three doses to 60 percent. The most important targets for treating lung disease are two types of epithelial cells—rod cells and ciliated cells—each transfected at a rate of about 15 percent.
The new particles also break down quickly, allowing them to clear from the lungs within a few days and reducing the risk of inflammation. If repeated doses are required, granules can also be delivered multiple times to the same patient. The team is now working to make the nanoparticles more stable so that they can be inhaled using nebulizers.