Researchers at the University of California at San Diego developed a new mRNA delivery technique. The method involves influenza virus-inspired nanoparticles that can escape from endosomes, acid vesicles that swallow and destroy materials that try to enter cells. Nanoparticles contain a protein receptor that allows them to unblock endosomes and release mRNA inside cells. The technology could enable more efficient and effective mRNA therapies.
With the COVID-19 vaccine program, mRNA enjoys a moment in the spotlight, as it acts as the centerpiece for some of the most effective COVID-19 vaccines. This nucleic acid provides some of the capabilities of gene therapies without many of the complications, due to its short duration of expression and its direct translation into protein without affecting the rest of the genetic material of a cell.
Previously thought to be too fragile for clinical use, mRNA has proven to be an effective therapy, but introducing it into cells remains a challenge. A common obstacle to nanotherapy is endosomal destruction, whereby therapy never escapes the covering endosome as it enters the cell membrane and is destroyed by the acidic environment. which is inside. For these nanotechnologies, escaping the endosome is a prerequisite for biological activity within the cell.
“Current mRNA delivery methods do not have very effective endosomal escape mechanisms, so the amount of mRNA that is actually released into cells and shows effects is very low,” said Liangfang Zhang, researcher involved in the study, in a press release. “Most of them are wasted when they are managed.”
Fortunately, there is a natural nanoparticle that is very adept at endosomal escape and that provided the model for this advanced mRNA delivery technology: the flu virus. Influenza viruses have evolved to be highly skilled at entering cells. They have a protein receptor on their surface, called hemagglutinin, which allows them to fuse with the endosome and open it. These researchers used the same protein to maximize the endosomal escape of mRNA.
They cultured genetically modified cells expressing the hemagglutinin protein on the surface of their membrane and then broke the membrane into small pieces so that it could function as a nanoparticle carrier for the payload of mRNA. Improving endosomal escape in this way could mean greater efficacy and reduce the side effects of mRNA therapies.
“Achieving efficient endosomal leakage would be a game changer for vaccines and mRNA therapies,” Zhang said. “If you can introduce more mRNA into your cells, that means you can take a much lower dose of an mRNA vaccine, and that could reduce side effects while achieving the same effectiveness.”
Study a Angewandte Chemie International Edition: Cell membrane-coated nanoparticles that mimic viruses for cytosolic mRNA delivery