Capped circular RNA and branched lipid nanoparticle extend gene expression in mice

Researchers at Nagoya University, working with FUJIFILM, have developed a capped circular RNA (Cap-cirRNA) that merges the stability of circular RNA with the efficient translation initiation of linear messenger RNA. Circular RNA lacks free ends, making it resistant to degradation, but its translation efficiency is typically lower because it relies on internal ribosome entry sites rather than a 5' cap. The team engineered a cap structure onto the circular RNA, enabling cap-dependent translation while retaining the molecule's durability.

To deliver both linear mRNA and the new Cap-cirRNA, the researchers used a novel lipid nanoparticle designated FL0445-LNP, supplied by FUJIFILM's Bioscience & Engineering Laboratories. Unlike conventional lipid nanoparticles with linear lipid chains, FL0445-LNP incorporates branched biodegradable chains in its core. This architecture provides greater internal flexibility, allowing the particle to encapsulate nucleic acids of varying sizes and structures.

In mouse experiments, FL0445-LNP achieved a tenfold increase in mRNA activity compared with standard lipid nanoparticles while eliciting a negligible inflammatory response. The researchers then tested delivery of glucagon-like peptide-1 (GLP-1) coding sequences using both linear mRNA and Cap-cirRNA formulated in FL0445-LNP. Both formats produced functional GLP-1 in vivo, but Cap-cirRNA demonstrated higher functional activity, suggesting longer-lasting expression from a single dose.

GLP-1 therapies such as Ozempic and Wegovy currently require repeated subcutaneous injections of the peptide. An mRNA or circular RNA approach would instruct the body's own cells to produce the peptide, potentially reducing injection frequency. The study shows proof of concept for this strategy, though the authors note that further optimization is needed to fine-tune Cap-cirRNA performance.

Beyond metabolic disease, the researchers say the combined platform could accelerate development of cancer vaccines, genome-editing tools, and protein-replacement therapies for genetic disorders. The work was published in Cell Biomaterials.