Researchers at the University of California, San Diego developed a new mRNA delivery technique. The method involves influenza virus-inspired nanoparticles that can escape endosomes, the acidic vesicles that engulf and destroy materials that try to enter cells. Nanoparticles contain a protein receptor that allows them to unblock endosomes and release mRNA into cells. The technology could enable more efficient and effective mRNA therapies.
With the COVID-19 vaccine program, mRNA is enjoying a moment in the limelight as it acts as the engine behind 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 in a cell.
Once thought to be too fragile for clinical use, mRNA has proven to be an effective treatment, but getting it into cells remains a challenge. A common obstacle for nanotherapeutics is endosome destruction, whereby the therapeutic never escapes the overlying endosome by entering through the cell membrane and is instead destroyed by the acidic environment within. For such 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 effect is very low,” said Liangfang Zhang, a researcher involved in the study, in a press release. “Most of them are wasted when administered.”
Fortunately, there is a naturally occurring nanoparticle that is very adept at endosomal escapement and provided the blueprint for this advanced mRNA delivery technology: the influenza virus. Influenza viruses have evolved to be highly capable of entering cells. They have a protein receptor on their surface, called hemagglutinin, which allows them to fuse with the endosome and break it down. These researchers used the same protein to maximize the endosomal escape of the mRNA.
They grew genetically engineered 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 mRNA payload. Improving endosomal escapement in this way could mean greater efficacy and reduced side effects of mRNA therapies.
“Achieving efficient endosomal escape would be a game changer for mRNA vaccines and therapies,” Zhang said. “If you can get more mRNA into cells, this means you can take a much lower dose of an mRNA vaccine, and this could reduce side effects and be just as effective.”
To study in Angewandte Chemie International Edition: Cell membrane-coated nanoparticles that mimic viruses for cytosolic mRNA delivery