American engineers have designed a new type of nanoparticles that can be used in the lungs, where they can deliver messenger RNA (mRNA) encoding useful proteins. With further development, these particles can provide an inhalable treatment for cystic fibrosis and other lung diseases. The study was published on March 30th in Nature Biotechnology. Daniel Anderson, a professor in the Department of Chemical Engineering at the Massachusetts Institute of Technology, said that this was the first demonstration of efficient delivery of RNA in the lungs of mice. Researchers hope it can 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 the CRISPR/Cas9 component, which may open the door to the design of therapeutic nanoparticles that can cut and replace pathogenic genes. In the new study, researchers set out to develop lipid nanoparticles that can target the lungs. These particles consist of two parts of molecules: a positively charged head base and a long lipid tail. The positive charge in the head base facilitates the interaction of particles with negatively charged mRNA, and also helps mRNA escape from the cellular structure that engulfs particles. At the same time, the lipid tail structure helps particles pass through the cell membrane. Researchers have proposed 10 different chemical structures for lipid tails, as well as 72 different head bases. By screening different combinations of these structures in mouse experiments, researchers were able to identify the structures most likely to reach the lungs. Research has shown that these particles can be used to transmit mRNA encoding the CRISPR/Cas9 component, which is designed to cut off the stop signals that are genetically encoded into animal lung cells. When the stop signal is removed, the fluorescent protein gene turns on. Measuring this fluorescence signal allows researchers to determine the percentage of cells that successfully express mRNA. The researchers found that after one dose of mRNA, about 40% of lung epithelial cells were transfected, two doses increased the level to over 50%, and three doses reached 60%. The most important targets for treating lung diseases are two types of epithelial cells - rod cells and ciliated cells, each of which is transfected at a rate of about 15%. New particles also decompose quickly, allowing them to be cleared from the lungs within a few days, and reducing the risk of inflammation. If repeated doses are required, the particles can also be delivered multiple times to the same patient. The team is now working to make nanoparticles more stable so they can be inhaled using an atomizer. (Liao Xinshe)