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

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A safer and more effective way of delivering mRNAs to the nose and lungs could lead to vaccines that provide better protection against respiratory infections such as covid-19, as well as superior treatments for lung conditions such as cystic fibrosis and asthma.

mRNAs, or messenger RNAs, are the templates for making proteins. By packaging them into small particles that don’t stick to mucus, Mark Saltzman at Yale University and his colleagues have increased the efficiency with which mRNAs can enter the cells lining the noses, throats and lungs of mice. “The mucus is a barrier,” says Saltzman. “The trick is to make the nanoparticles resistant to adhesion to the mucus.”

If mRNAs are added to cells, those cells can be made to produce any desired protein. The effect is only temporary, however, because mRNAs break down after days or weeks.

With mRNA vaccines, the desired protein is viral, as this trains the immune system to recognise and target that protein during a viral infection. There is also a lot of interest in using mRNAs to deliver beneficial proteins for treating inherited conditions. For instance, cystic fibrosis is caused by a build-up of mucus in the lungs due to mutations in a protein called CFTR. Efforts to treat it by getting mRNAs for working versions of CFTR into the lungs have shown promise.

However, naked mRNAs are destroyed before they can get into cells, so they are usually packaged in fatty particles. These lipid nanoparticles work well when injected, as done with the mRNA covid-19 vaccines, but they aren’t very good at getting through the mucus layer that protects the lungs when inhaled or administered as a nasal spray.

What’s more, larger doses of mRNAs are needed for treating conditions like cystic fibrosis than are used in vaccination, as the mRNAs need to get into a higher proportion of cells. Breathing in such large doses of lipid nanoparticles can cause lung inflammation.

Saltzman’s team has previously shown that mRNAs can be delivered to cells by packaging them in nanoparticles made of a mix of two kinds of polymer, instead of lipids. The researchers have now optimised this approach for delivering mRNAs to the lungs.

They created several versions of the polymer nanoparticles and used them to deliver an mRNA into mice, entering up to a fifth of the cells that line the animals’ noses, throats and lungs. This mRNA coded for a glowing protein called luciferase, and the lung tissue treated with their best-performing nanoparticles produced three orders of magnitude more light than tissue treated with an existing method of delivering mRNAs.

Next, mice that are especially susceptible to covid-19 were given an intranasal vaccine packed in the polymer nanoparticles. Around 70 per cent of these mice survived when given a massive dose of covid-19, whereas all non-vaccinated mice given the same dose died.

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

The hope is that vaccines delivered by an intranasal spray will provide better protection than standard intramuscular injections because they stimulate immunity at the surfaces that are the first to get exposed to viruses. The researchers didn’t directly compare their vaccine with a conventional one, but that is now being done, says Saltzman.

In people, an intranasal spray may not be sufficient for vaccination, says Lavelle. Devices such as nebulisers, which turn liquid medicine into a fine mist, might be needed to ensure the nanoparticles reach the lungs.

A company called Xanadu Bio has been set up to develop vaccines based on this technology for respiratory conditions, including flu and respiratory syncytial virus (RSV). Saltzman’s team is also working on treatments for cystic fibrosis, he says.

If the polymer nanoparticles were used to deliver a working version of the CFTR protein, regular treatments would be required, but the nanoparticles could also be used to deliver mRNAs coding for proteins that correct mutated CFTR genes, which would have a longer-term effect, says Saltzman.

He points out, however, that cystic fibrosis often affects other parts of the body besides the lungs, so treating the lungs only wouldn’t provide a complete cure.


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