Advancements in Lipid Nanoparticles for Targeted Gene Therapy in the Lungs

Researchers from MIT and the University of Massachusetts Medical School have developed a new type of lipid nanoparticle designed to deliver messenger RNA (mRNA) to the lungs. This innovative approach could potentially provide an inhalable treatment for cystic fibrosis and other lung diseases.

The team, led by Daniel Anderson, a professor in MIT's Department of Chemical Engineering, demonstrated highly efficient delivery of RNA to the lungs in mice. The study, published in Nature Biotechnology, showed that these lipid nanoparticles can be used to deliver mRNA encoding CRISPR/Cas9 gene-editing components. This development could pave the way for therapeutic nanoparticles capable of replacing disease-causing genes.

A major challenge in deploying mRNA as a therapeutic for treating diseases caused by faulty genes has been delivering it to the right part of the body without off-target effects. Lipid nanoparticles, with their fatty sphere structure, protect mRNA from being broken down prematurely and assist in its entry into target cells. However, until now, specifically targeting the lungs has been difficult.

In this study, the researchers developed lipid nanoparticles with a unique molecular structure consisting of a positively charged headgroup and a long lipid tail. The positive charge of the headgroup allows interaction with negatively charged mRNA and assists in mRNA escape from cellular structures. The lipid tail structure enables the particles to pass through the cell membrane.

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After screening various combinations of these structures in mice, the researchers identified the most likely candidates to reach the lungs. Tests revealed that after a single dose of mRNA, approximately 40% of lung epithelial cells were transfected. This percentage increased to over 50% after two doses and up to 60% following three doses. Importantly, the cells that were successfully edited are the most relevant for treating lung disease, such as club cells and ciliated cells.

These newly designed lipid nanoparticles have several advantages over existing delivery methods. They break down quickly, enabling clearance from the lung within a few days and reducing the risk of inflammation. They can also be administered multiple times to the same patient if needed. In comparison, adenoviruses, another mRNA delivery method, can't be given repeatedly due to their induction of an immune response.

As part of their ongoing research, the scientists are working on enhancing the stability of their nanoparticles to allow for aerosolization and inhalation using a nebulizer. They also plan to test the lipid nanoparticles in a mouse model of cystic fibrosis, as well as develop treatments for other lung diseases like idiopathic pulmonary fibrosis and mRNA vaccines that can be delivered directly to the lungs.

This work in lipid nanoparticles for targeted gene editing in the lungs has the potential to improve treatment options for various lung diseases, providing new hope to patients suffering from these debilitating conditions.