Nanoparticle could deliver genetic therapy to lungs, study finds

Researchers used such fatty molecules to send RNA therapy to mice's lungs

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

Share this article:

Share article via email
A handful of mice are pictured clustered together.

A lipid nanoparticle designed to deliver genetic therapy to lung cells could be used as a platform to treat lung-related diseases like cystic fibrosis (CF), a mouse study found.

Researchers developed a way to identify lipid nanoparticles — fatty molecules that help deliver genetic material to cells — that are likely to bind to the lungs, instead of the liver, where they usually head.

“Being able to target the lungs is potentially life-changing for someone with lung cancer or cystic fibrosis,” Michael Mitchell, PhD, a professor at the University of Pennsylvania and senior author of the study, said in a university press release.

The researchers described their findings in the study, “High-throughput barcoding of nanoparticles identifies cationic, degradable lipid-like materials for mRNA delivery to the lungs in female preclinical models,” published in Nature Communications.

Recommended Reading
banner for Lara Govendo's column

Thinking about death is normal for me as a CF and transplant patient

Targeting a nanoparticle to deliver treatments for diseases like CF

Lipid nanoparticles can function like delivery wrapping paper to help get genetic material to cells. In theory, these nanoparticles could be a useful platform to develop treatments for genetic disorders like CF.

Studies have explored using lipid nanoparticles to deliver healthy messenger RNA (mRNA) from the CFTR gene to cells, which could allow cells to make a functional version of the CFTR protein, a defective version of which causes CF.

For this approach to work, the nanoparticles would need to deliver their genetic payload to the cells most impacted by CF — meaning the lungs. But when most lipid nanoparticles are administered into the body, they end up binding to the liver.

“The way the liver is designed, [lipid nanoparticles] tend to filter into hepatic cells, and struggle to arrive anywhere else,” Mitchell said.

Previous research had shown that cationic lipid nanoparticles — particles with a positive electrical charge — are generally able to get into the lungs better than other types of nanoparticles. However, cationic nanoparticles also are frequently toxic: Cell membranes hold a negative charge, and if the nanoparticle has too strong a positive charge, it can tear apart the cell.

The Penn researchers sought to identify a cationic lipid nanoparticle that could bind to the lungs without causing undue cellular toxicity.

The team synthesized a library of 180 different nanoparticle variations, first testing their ability to deliver mRNA into cells in a dish. To make the experiments easier to run quickly, the researchers delivered mRNA encoding luciferase, the enzyme that lets fireflies glow. When the nanoparticles successfully delivered mRNA to the cells, the cells would light up.

Recommended Reading
An illustration shows three cells floating in the air.

New nanoparticles may correct genetic defects in lungs

Barcoding DNA shows how a nanoparticle can deliver therapy

The researchers selected 96 nanoparticles for further testing in female mice, then used a technique called DNA barcoding to track where each of the nanoparticles went. They attached a unique sequence of DNA to each type of nanoparticle before injecting the nanoparticle into the mice, so that instead of looking for each type of nanoparticle, they could scan the barcoded DNA to determine which nanoparticles went to the lungs.

The experiments identified 21 nanoparticles that were able to get into the lungs with reasonable efficacy, and the researchers zeroed in on one, LNP-CAD9, as the most promising.

The team then used these nanoparticles to deliver an RNA-based therapy to mice with lung cancer, showing the technique could slow tumor growth and extend survival.

“These findings demonstrate that high-throughput barcoding technology can be utilized as an efficient and effective screening tool for identifying structurally distinct nanoparticles for extrahepatic [outside-the-liver] delivery to the lung,” the scientists wrote.

“This technology will help to accelerate the development of mRNA therapeutics beyond the liver,” said Lulu Xue, PhD, a postdoctoral fellow at Penn and the first author on the paper.