Illustration of flu virus-mimicking nanoparticle releasing and getting in mRNA into a host cell (top). An unique protein on the nanoparticles surface triggers it to fuse with the endosomal membrane, permitting its mRNA freight to securely get away into the host cell (bottom). The work addresses a significant challenge in the field of drug delivery: getting big biological drug molecules securely into cells and protecting them from organelles called endosomes. To make the nanoparticles, the researchers genetically engineered cells in the lab to reveal the hemagglutinin protein on their cell membranes. They then separated the membranes from the cells, broke them into small pieces, and covered them onto nanoparticles made from a biodegradable polymer that has actually been pre-packed with mRNA particles inside.
Illustration of influenza virus-mimicking nanoparticle launching and entering mRNA into a host cell (top). An unique protein on the nanoparticles surface activates it to fuse with the endosomal membrane, enabling its mRNA freight to securely leave into the host cell (bottom). Credit: Angewandte Chemie International Edition
Nanoengineers at the University of California San Diego have developed a new and possibly more efficient way to provide messenger RNA (mRNA) into cells. Their technique includes packing mRNA inside nanoparticles that mimic the flu infection– a naturally efficient car for providing hereditary product such as RNA inside cells.
The new mRNA delivery nanoparticles are described in a paper published just recently in the journal Angewandte Chemie International Edition.
The work addresses a significant challenge in the field of drug shipment: getting large biological drug molecules safely into cells and protecting them from organelles called endosomes. These small acid-filled bubbles inside the cell act as barriers that trap and absorb large particles that try to go into. In order for biological therapeutics to do their job once they are inside the cell, they require a method to get away the endosomes.
” Current mRNA shipment techniques do not have very effective endosomal escape mechanisms, so the quantity of mRNA that actually gets launched into cells and reveals result is very low. Most of them are lost when they get administered,” said senior author Liangfang Zhang, a teacher of nanoengineering at the UC San Diego Jacobs School of Engineering.
Accomplishing efficient endosomal escape would be a video game changer for mRNA vaccines and therapies, discussed Zhang. “If you can get more mRNA into cells, this suggests you can take a much lower dosage of an mRNA vaccine, and this might lower negative effects while accomplishing the exact same efficacy.” It might also improve shipment of little interfering RNA (siRNA) into cells, which is utilized in some kinds of gene treatment.
In nature, infections do an extremely good task of leaving the endosome. The influenza An infection, for example, has an unique protein on its surface called hemagglutinin that, when activated by acid inside the endosome, activates the virus to fuse its membrane with the endosomal membrane. This opens the endosome, allowing the virus to launch its hereditary product into the host cell without getting damaged.
Zhang and his team developed mRNA delivery nanoparticles that imitate the flu infections capability to do this. To make the nanoparticles, the researchers genetically crafted cells in the lab to reveal the hemagglutinin protein on their cell membranes. They then separated the membranes from the cells, broke them into small pieces, and covered them onto nanoparticles made from a biodegradable polymer that has actually been pre-packed with mRNA particles inside.
The ended up product is a flu virus-like nanoparticle that can enter into a cell, break out of the endosome, and complimentary its mRNA payload to do its task: instruct the cell to produce proteins.
The nanoparticles were loaded with mRNA encoding for a bioluminescent protein called Cypridina luciferase. This was evidence that the influenza virus-like nanoparticles efficiently delivered their mRNA payloads into cells in vivo.
The scientists are now testing their system for shipment of healing mRNA and siRNA payloads.
Reference: “Virus-Mimicking Cell Membrane-Coated Nanoparticles for Cytosolic Delivery of mRNA” by Joon Ho Park, Animesh Mohapatra, Jiarong Zhou, Maya Holay, Nishta Krishnan, Dr. Weiwei Gao, Dr. Ronnie H. Fang, Prof. Liangfang Zhang, 25 October 2021, Angewandte Chemie International Edition.DOI: 10.1002/ anie.202113671.
This work is supported by the Defense Threat Reduction Agency Joint Science and Technology Office for Chemical and Biological Defense (grant HDTRA1-18-1-0014 and HDTRA1-21-1-0010).
