Scientists Successfully Delivered mRNA into cells by Flu virus inspired nanoparticles

Nanoengineers at the University of California, San Diego, have created a new and potentially more successful method of delivering messenger RNA (mRNA) into cells. Their method involves packaging mRNA within flu-like nanoparticles, which are a natural vehicle for transferring genetic material like RNA inside cells.

A report just published in the journal Angewandte Chemie International Edition describes the new mRNA delivery nanoparticles.

The research tackles a significant problem in medication delivery: delivering large biological drug molecules into cells safely while also shielding them from endosomes. Large molecules that try to enter the cell are trapped and digested by these tiny acid-filled bubbles inside the cell. Biological therapies require a method to escape the endosomes in order to execute their job once inside the cell.

"Due to the lack of effective endosomal escape mechanisms in current mRNA delivery techniques, the amount of mRNA that actually gets released into cells and has an effect is relatively low. When they're given out, the vast majority of them are thrown away "Liangfang Zhang, a professor of nanoengineering at the UC San Diego Jacobs School of Engineering, is the senior author.

Zhang highlighted that achieving efficient endosomal escape would be a game changer for mRNA vaccines and therapeutics. "If you can get more mRNA into cells, you can take a lot lower dose of an mRNA vaccine and still achieve the same efficiency," says the researcher. It may also help in the transport of small interfering RNA (siRNA), which is utilised in some types of gene therapy.

Viruses are highly good at escaping the endosome in nature. Influenza is a virus that causes illness. A virus, for example, includes a protein called hemagglutinin on its surface that, when activated by acid inside the endosome, causes the virus's membrane to merge with the endosomal membrane. This allows the virus to transfer its genetic material into the host cell without being killed by the endosome.

Zhang and his colleagues created mRNA delivery nanoparticles that mimic the capabilities of the flu virus to do so. The researchers genetically altered cells in the lab to express the hemagglutinin protein on their cell membranes in order to generate the nanoparticles. The membranes were then taken from the cells, broken into little pieces, and coated onto nanoparticles comprised of a biodegradable polymer that had been pre-packed with mRNA molecules within.

The final product is a flu virus-like nanoparticle that can enter a cell, break free from the endosome, and allow its mRNA payload to complete its job, which is to tell the cell to make proteins.

The nanoparticles were tested on mice by the researchers. The nanoparticles contained mRNA that encoded for Cypridina luciferase, a bioluminescent protein. They were given to the mice through intravenous injection and through the nose (the mice breathed droplets of a nanoparticle-containing solution sprayed to their nostrils). The researchers examined the mice's nostrils and blood and discovered a substantial amount of bioluminescence signal. This demonstrated that the flu virus-like nanoparticles delivered their mRNA payloads to cells in vivo.

The researchers are currently putting their system to the test to see if it can deliver therapeutic mRNA and siRNA payloads.

Reference:

Joon Ho Park, Animesh Mohapatra, Jiarong Zhou, Maya Holay, Nishta Krishnan, Weiwei Gao, Ronnie H. Fang, Liangfang Zhang. Virus‐Mimicking Cell Membrane‐Coated Nanoparticles for Cytosolic Delivery of mRNA. Angewandte Chemie International Edition, 2021; DOI: 10.1002/anie.202113671