Inhaled Nanoparticles Could Help Lung CFTR Production, Study Says

Lipid nanoparticles proving effective in mouse study, Oregon researchers report

Patricia Valerio, PhD avatar

by Patricia Valerio, PhD |

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Researchers in Oregon have developed lipid nanoparticles that can be inhaled and effectively deliver messenger ribonucleic acid (mRNA) into the lungs of mice, triggering the cells to produce the defective protein in cystic fibrosis (CF).

“Inhaled [lipid nanoparticles] resulted in localized protein production in the mouse lung without toxicity, either in the lungs or systemically, and repeated administration led to sustained protein production in the lungs,” Gaurav Sahay, the study’s senior author and an associate professor of pharmaceutical sciences at Oregon State University, said in an Oregon State University press release.

The study, “Engineering Lipid Nanoparticles for Enhanced Intracellular Delivery of mRNA through Inhalation,” was published in ACS Nano. It was supported by the National Heart, Lung, and Blood Institute and the Cystic Fibrosis Foundation.

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CF is caused by alterations in the CF transmembrane conductance regulator (CFTR) gene, which results in a defective CFTR protein. This deficiency leads to lung dehydration and mucus buildup that ultimately blocks the airways.

In 2018, Sahay and other researchers in Oregon showed the value of a new potential therapy: lipid (fat) nanoparticles (tiny particles) filled with functional CFTR mRNA (genetic material for protein synthesis), with potential to be inhaled at home.

“Lipid nanoparticles have been successful in delivering mRNA in vaccines, but an inhalation-based mRNA therapy has continued to be a challenge,” Sahay said. One of the problems is that lipid nanoparticles “tend to break apart from shear stress during aerosolization, which leads to ineffective delivery,” Sahay added.

The solution would involve creating lipid nanoparticles strong enough to go through nebulization — a process that transforms a liquid into a mist that can be inhaled — and able to pass the mucus, reach the lung cells, and deliver the CFTR cargo to perform its duty.

In 2020, Sahay co-authored another study showing that phytosterols, or nanoparticles built with plant-based molecules similar to cholesterol (a fatlike substance), were better at delivering their content in cells.

New developments

Now, Sahay and colleagues have used beta-sitosterol with a polyethylene glycol (PEG) lipid — used to increase the stability of the nanoparticles, as well as their mucus penetration action — to overcome the previous challenges of durability and mobility of the particles.

“Increase[d] PEG concentrations in the [lipid nanoparticles] made for better shear resistance and mucus penetration,” Sahay said.

When tested in cells, the nanoparticles showed a uniform distribution, suitable chemical three-dimensional shape, and fast spreading with a higher release of CFTR mRNA.

When tested in a mouse model, the inhaled nanoparticles showed no signs of toxicity in the lungs or other body parts. In addition, repeated administration of these inhaled nanoparticles triggered controlled CFTR production in the lungs.

The particles were also tested in mice that were CFTR-deficient, resulting in a successful lung expression of the protein.

Overall, “this study demonstrated the rational design approach for clinical translation of inhalable [lipid nanoparticles]-based mRNA therapies,” the researchers wrote.

Sahay and four other members from Oregon State University launched the Center for Innovative Drug Delivery and Imaging (CIDDI) at the Oregon Health & Science University’s Robertson Life Sciences Building to further expand these therapies.

CIDDI received a $700,000 grant from the M.J. Murdock Charitable Trust for equipment for a manufacturing facility and an additional $600,000 from the Oregon Health & Science University and Oregon State University.

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