Engineers from MIT and the University of Massachusetts Medical School have achieved effective delivery of RNA to mice lungs through the development of nanoparticles. These nanoparticles are programmed to convey mRNA that encodes CRISPR/Cas9 gene-editing machinery, which has the potential to replace genes that cause illness, as per the report of the Laboratory Equipment.
Two parts make up the lung-directed lipid nanoparticles: a positive headgroup and a long lipid tail. These components interact with the mRNA charge, encouraging it to escape enclosed cellular structures and aiding the particles' passage through the cell membrane.
Designing Nanoparticles That Can Deliver mRNA to the Lungs
Messenger RNA (mRNA) has the potential to treat genetic diseases, but its deployment has been limited due to the challenge of delivering it to the right part of the body without causing off-target effects. Lipid nanoparticles have been used to encapsulate mRNA for the effective transfection of target cells, EurekAlert! reported.
Clinical trials evaluating mRNA treatments for liver diseases and mRNA-based COVID-19 vaccines injected into muscle tissue have shown success. However, to target lung cells for inhalation into the lungs, there is a need for more efficient and potent particles.
MIT Professor Daniel Anderson and his lab aimed to create particles that could more effectively deliver genetic material to the epithelial cells in the lungs, resulting in the creation of polymer nanoparticles that could deliver mRNA encoding a bioluminescent protein to lung cells.
In the new study, titled "Combinatorial Design of Nanoparticles for Pulmonary mRNA Delivery and Genome Editing" published in Nature Biotechnology, the team developed lipid nanoparticles that could target lungs.
However, the team sought to improve on this with the development of lipid nanoparticles with a positively charged headgroup and a long lipid tail to interact with mRNA and escape cellular structures upon entering cells.
Using 10 different lipid tail structures and 72 different headgroups, the researchers were able to identify the combinations most likely to reach the lungs through screening tests in mice.
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Nanoparticles Efficiently Deliver mRNA to the Lungs
Further tests showed that the researchers were able to create a new lipid nanoparticle delivery system, which could allow easier and more efficient delivery of mRNA to the lungs, Science Daily reports. Early tests showed that the nanoparticles could deliver mRNA to cut out a genetically encoded "stop signal" in mouse lung cells.
After up to three doses, as many as 60% of transfected lung epithelial cells were able to remove the stop signal and express the mRNA. The most important cells for treating lung disease were transfected at about 15%. The new system could deliver repeat doses as necessary, providing an advantage over a modified adenovirus system which stimulates an immune response in the host.
The researchers plan to develop their nanoparticles to allow them to be aerosolized and inhaled using a nebulizer, to treat genetic mutations including those which cause cystic fibrosis, and idiopathic pulmonary fibrosis, and to deliver mRNA vaccines directly to the lungs.
The injected particles also break down easily and quickly within the lungs, greatly reducing the threat of inflammation, and have the potential to offer a more stable method of delivery than other methods that have previously been tested. The new nanoparticle delivery system could replace the use of modified adenoviruses to deliver mRNA to the lungs.
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