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Inhaled mRNAs to Enhance Vaccines and Therapies for Lung Diseases

A lipid nanoparticle carrying the mRNA of a virus entering a cell

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A more effective and safer method of delivering mRNAs to the nose and lungs offers the potential to enhance vaccines for respiratory infections, such as covid-19, and improve treatments for lung conditions like cystic fibrosis and asthma.

mRNAs, also known as messenger RNAs, serve as templates for protein synthesis. By encapsulating them in particles that do not adhere to mucus, Mark Saltzman and his team at Yale University have increased the efficiency of mRNAs entering the cells lining the respiratory system. Saltzman explains that “the mucus is a barrier” and that the key is to make nanoparticles resistant to mucus adhesion.

When introduced into cells, mRNAs enable the production of desired proteins. However, this effect is only temporary because mRNAs break down within days or weeks.

mRNA vaccines utilize viral proteins to train the immune system to recognize and target specific proteins during viral infections. Using mRNAs to deliver beneficial proteins for treating genetic conditions has also garnered considerable interest. For example, efforts to treat cystic fibrosis have shown promise by introducing mRNAs for functional versions of the CFTR protein into the lungs to address mucus buildup caused by CFTR mutations.

Naked mRNAs are prone to destruction before entering cells, so they are typically encased in lipid nanoparticles. While these lipid nanoparticles are effective when injected, as seen in mRNA COVID-19 vaccines, they struggle to penetrate the protective mucus layer of the lungs when inhaled or administered as a nasal spray.

Additionally, higher doses of mRNAs are required to treat conditions like cystic fibrosis compared to vaccination, as a larger proportion of cells need to receive the mRNAs. However, inhaling such large doses of lipid nanoparticles can lead to lung inflammation.

Saltzman and his team have previously demonstrated that mRNAs can be delivered to cells using nanoparticles made from a combination of two types of polymers, instead of lipids. They have now optimized this approach for mRNA delivery to the lungs.

Various versions of polymer nanoparticles were created and employed to deliver an mRNA into mice, successfully entering up to 20% of the cells lining their respiratory systems. The mRNA encoded a luminescent protein called luciferase, and the lung tissue treated with the best-performing nanoparticles emitted three orders of magnitude more light than tissue treated with the conventional mRNA delivery method.

In the next step, mice highly susceptible to COVID-19 were given an intranasal vaccine packaged in the polymer nanoparticles. Remarkably, approximately 70% of these vaccinated mice survived after receiving a massive dose of COVID-19, while all non-vaccinated mice given the same dose perished.

“The protection shown is impressive,” comments Ed Lavelle at Trinity College Dublin. “It appears to be a significant step forward in terms of mucosal mRNA vaccines.”

The hope is that intranasal spray vaccines will offer better protection compared to standard intramuscular injections because they stimulate immunity at the first points of contact with viruses. While the researchers did not directly compare their vaccine with conventional ones, Saltzman states that such a comparison is currently underway.

However, Lavelle suggests that an intranasal spray alone may not be sufficient for vaccination in humans. Devices such as nebulizers, which convert liquid medicine into a fine mist, might be necessary to ensure that the nanoparticles reach the lungs.

Xanadu Bio, a company established to develop vaccines for respiratory conditions, including flu and respiratory syncytial virus (RSV), is utilizing this technology. Saltzman’s team is also working on treatments for cystic fibrosis.

In the case of delivering a functional CFTR protein using the polymer nanoparticles, regular treatments would be required. However, these nanoparticles could also transport mRNAs coding for proteins that correct mutated CFTR genes, resulting in a longer-term effect, according to Saltzman.

Nevertheless, Saltzman points out that cystic fibrosis often affects other body parts besides the lungs. Therefore, treating only the lungs would not provide a complete cure.

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