Nanoengineers use influenza virus shells to improve the delivery of mRNA to cells

Endosomal flight

Illustration of influenza virus-like nanoparticle entering and releasing mRNA into a host cell (top). A special protein on the surface of the nanoparticles causes it to fuse with the endosomal membrane, allowing its mRNA load to escape safely into the host cell (bottom). Credit: Applied Chemistry International Edition

Nanoengineers at the University of California San Diego have developed a new and potentially more efficient way to deliver messenger RNA (mRNA) into cells. Their approach involves packaging mRNA inside nanoparticles that mimic the flu virus – a naturally effective means of delivering genetic material such as RNA inside cells.

The new mRNA delivery nanoparticles are described in a paper recently published in the journal Applied Chemistry International Edition.

The work addresses a major challenge in drug delivery: getting large biological drug molecules safely into the cells and protecting them from organelles called endosomes. These little ones acid-filled bubbles inside the cell serve as barriers that capture and digest large molecules that try to penetrate. In order for biological drugs to perform their work once inside the cell, they need a way to escape the endosomes.

“Current mRNA delivery methods do not have very efficient endosomal escape mechanisms, so the amount of mRNA that is actually released into cells and shows efficacy is very low. The majority of them are wasted when administered,” said senior author Liangfang Zhang, Professor of Nanotechnology at UC San Diego Jacobs School of Engineering.

Achieving effective endosomal escape would be a game changer for mRNA vaccines and therapies, Zhang explained. “If you can get more mRNA into the cells, it means you can take a much lower dose of an mRNA vaccine, and this can reduce side effects while achieving the same effect.” It could also improve the delivery of small interfering RNA (siRNA) to cells used in some forms of gene therapy.

In nature, viruses do a very good job of escaping the endosome. For example, the influenza A virus has a special protein on the surface called hemagglutinin, which, when activated by acid inside the endosome, causes the virus to fuse its membrane with the endosomal membrane. This opens the endosome, allowing the virus to release its genetic material into the host cell without being destroyed.

Zhang and his team developed mRNA delivery nanoparticles that mimic the ability of the flu virus to do this. To make the nanoparticles, the researchers genetically engineered cells in the laboratory to express the hemagglutinin protein on their cell membranes. They then separated the membranes from the cells, breaking them into tiny pieces and coating them on nanoparticles made of a biodegradable polymer that has been packed with mRNA molecules inside.

The finished product is an influenza virus-like nanoparticle that can penetrate a cell, break out of the endosome, and release its mRNA payload to perform its job: instructing the cell to produce proteins.

The researchers tested the nanoparticles in mice. The nanoparticles were packed with mRNA encoding a bioluminescent protein called Cypridina luciferase. They were administered both through the nose – the mice inhaled drops of a solution containing nanoparticles applied to the nostrils – and via intravenous injection. The researchers imaged the noses and analyzed the mice’s blood and found a significant amount of bioluminescence signal. This was evidence that the influenza virus-like nanoparticles efficiently delivered their mRNA payload to cells in vivo.

The researchers are now testing their system for the delivery of therapeutic 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, October 25, 2021, Applied Chemistry 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 (grants HDTRA1-18-1-0014 and HDTRA1-21-1-0010).

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