Researchers at the University of California San Diego have developed a new technique for delivering mRNA. The method involves flu virus-inspired nanoparticles that can escape the endosomes, the acidic vesicles, that envelop and destroy materials that try to enter cells. The nanoparticles contain a protein receptor that enables them to unlock the endosomes and release the mRNA inside the cell. 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 powerhouse behind some of the most effective COVID-19 vaccines. This nucleic acid offers some of the capabilities of genetic therapies without many of the complications of its short duration of expression and its direct translation into protein without affecting the rest of the genetic material in a cell.
Previously thought to be too fragile for clinical use, mRNA has been shown to be an effective therapeutic, but getting it into cells is still a challenge. A common hurdle for nanotherapeutic agents is endosomal destruction, in which the therapeutic agent never escapes the endosome that covers it when entering the cell membrane, but is instead destroyed by the acidic environment inside. For such nanotechnologies, the escape of 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 has an effect is very small,” 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 good at endosomal escape and that provided the blueprint for this advanced mRNA transport technology – the influenza virus. Influenza viruses have evolved into highly skilled cells. They have a protein receptor called hemagglutinin on their surface, which enables them to fuse with the endosome and break it open. These researchers used the same protein to maximize endosomal escape of the mRNA.
They cultured genetically engineered cells that express the hemagglutinin protein on their membrane surface, and then broke the membrane into small pieces so that it could act as a nanoparticle carrier for the mRNA payload. Such an improvement in endosomal escape could mean increased effectiveness and fewer side effects for mRNA therapies.
“Achieving efficient endosomal escape would be a tipping point for mRNA vaccines and therapies,” said Zhang. “If you can get more mRNA into the cells, it means you can take a much lower dose of an mRNA vaccine, which could reduce side effects while being as effective.”
Study in Angewandte Chemie International Edition: Virus-mimicking cell membrane-coated nanoparticles for the cytosolic transport of mRNA