A crucial part of the success of mRNA vaccines in combating the COVID-19 pandemic was finding a way to insert delicate mRNA strands into our cells. The answer was a class of molecular vehicles named Lipid Nanoparticles (LNP). These microscopic fat bubbles encased mRNA strands, allowing our cells to gulp them in. Once inside, the LNPs released mRNA for gene translation into SARS-Cov-2’s spike proteins, triggering an immune response that helped prepare our defenses against the virus.
A stronger mRNA payload…
Linear mRNA strands carry a cap end and a tail end, which guide ribosomes to initiate the translation of genes into proteins. But degradation enzymes within the cell can also use the same terminal points to attack and break down the mRNA. cirRNA, being a loop, does not have any start or end point. It is thus more resistant to degradation. Additionally, without a specific “stop” marker, ribosomes can keep riding this loop to code for proteins. This makes cirRNA capable of driving gene expression for longer times.
On the other hand, cirRNA relies on internal instructions within its loop for gene translation. As a result, its gene expression efficacy can be lower compared to mRNA’s cap and end marker system.
To counter this, Hiroshi Abe, Seigo Kimura, and their team at Nagoya University’s Integrated Research Consortium on Chemical Sciences (IRCCS) and the Department of Chemistry perfected making a cirRNA with a cap-end. Called Cap-cirRNA, it “combines the strengths of mRNA and cirRNA to provide durability and efficient (gene) translation for a longer time,” Abe explains.
…Gets a new ride into the cell
Next, Abe and his team needed a delivery vehicle that could transport both linear mRNA and their Cap-cirRNA into a cell. For this, they obtained a new lipid nanoparticle called FL0445-LNP from researchers at the Bioscience & Engineering Laboratories at FUJIFILM Corporation. LNPs are similar to soap micelles, with a protective lipid core that houses mRNA material while its outer surface interacts with the aqueous cell environment and cell membrane. Once inside, the LNP is designed to be biodegradable to make the mRNA available for its translation duties.
As far as LNPs go, FL0445-LNP is an all-rounder. Its lipid interior features branched biodegradable chains compared to conventional LNPs which have linear chains. The researchers found that this architecture adds more internal flexibility, allowing FL0445-LNP to carry a variety of light, heavy, and structurally different nucleic acids.
Additionally, using FL0445-LNP showed a 10-fold increase in mRNA activity while causing negligible inflammatory response compared to conventional LNPs.
“Once you have figured out a common way to safely deliver stronger or more durable mRNA, then that opens up many more possibilities,” says Seigo Kimura, assistant professor at Nagoya University and the lead author of this study.
GLP-1 treatments, cancer vaccines, and more…
Armed with this vehicle, the researchers tested the delivery of both linear mRNA and Cap-cirRNA using FL0445-LNP. To do this, they chose Glucagon-like Peptide-1 (GLP-1) which is popular in obesity-treatment drugs such as Ozempic and Wegovy today. These drugs administer the peptide via subcutaneous injection.
But mRNA holds the promise of directly sending the code to produce this peptide to our cells. Paired with the durability of cirRNA, this can increase treatment durations and reduce the need for multiple injections.
The researchers successfully demonstrated the in-vivo administration of GLP-1 through both mRNA and Cap-cirRNA in mice using FL0445-LNP. Out of the two, Cap-cirRNA showed higher functional activity, but more research is needed to fine-tune this process.
Besides mRNA vaccines and GLP-1 treatments, Abe says this new Cap-cirRNA + FL0445-LNP technology can speed up drug discovery with potential applications in the development of cancer vaccines, genome editing, and protein supplements to treat genetic disorders.
Cell Biomaterials
Experimental study
Cells
A Branched Ionizable Lipid Nanoparticle Platform for Versatile In Vivo Delivery of Nucleic Acids: Validation from mRNA to Capped Circular RNA
19-Aug-2026
The authors declare no competing financial interest.