Nagoya University and Fujifilm Develop Next-Generation mRNA Delivery Technology with Circular RNA and Novel Lipid Nanoparticles
核心洞察
A Nagoya University and Fujifilm team developed "Cap-cirRNA," a circular mRNA with a cap structure combining high translation efficiency with long-term stability.
The delivery system uses Fujifilm's ionizable lipid FL0445, achieving more than 10 times the intracellular transport efficiency of conventional lipid nanoparticles.
In obese mice, circular mRNA encoding GLP-1 (搜索) produced prolonged protein expression, improved blood glucose control, and suppressed the inflammatory response.
A research team from Nagoya University and Fujifilm has developed a new drug delivery system (DDS) that efficiently transports messenger RNA (mRNA) into cells, achieving more than 10 times the transport efficiency of conventional approaches while suppressing side effects such as inflammation. The findings were published in the U.S. journal Cell Biomaterials.
The technology is expected to find applications in next-generation mRNA therapeutics, vaccines, and gene therapy. mRNA is a molecule that copies genetic information from DNA in the cell nucleus and directs the body to produce proteins according to that blueprint. Building on the success of COVID-19 vaccines, pharmaceutical products that encapsulate mRNA in lipid nanoparticles (LNP) for delivery into the body are increasingly reaching practical application.
Overcoming the Limitations of Linear mRNA
Conventional mRNA has a linear, string-like structure that is rapidly degraded in the body. The research team had previously developed "circular" mRNA, which resists degradation and can produce proteins over extended periods, but efficiently delivering it into cells remained a challenge. While circular RNA lacks starting and ending points and is less susceptible to enzymatic degradation, it also has the drawback of lower translation initiation efficiency compared to linear mRNA.
In this study, the team created "Cap-cirRNA" by adding a cap structure to circular RNA, producing a molecule that combines the high translation efficiency of linear mRNA with the long-term stability of the circular form.
A Novel Lipid Nanoparticle Carrier
For the LNP carrier, the team adopted the ionizable lipid "FL0445" developed by Fujifilm. FL0445 features a structure that is readily degraded within cells, and its branched lipid architecture provides flexibility in the internal space, making it well-suited for transporting the rigid structure of circular RNA. The team investigated optimal LNP compositions and produced novel LNPs encapsulating circular mRNA.
In experiments using cultured cells, intracellular transport efficiency reached more than 10 times that of conventional LNPs.
GLP-1 Delivery and Metabolic Effects in Obese Mice
To validate practical utility, the team encapsulated circular mRNA encoding the peptide hormone "GLP-1 (搜索)"—used in diabetes (搜索) treatment—into LNPs and administered them to obese mice. The results confirmed excellent blood glucose control, and the inflammatory response, a representative side effect of LNP-based drugs, was also suppressed.
GLP-1 (搜索) is currently widely used as a core component of obesity (搜索) treatments, but typically requires repeated injections. In the group of mice administered Cap-cirRNA, GLP-1 production persisted longer and blood glucose improvement was more pronounced compared to the group receiving linear mRNA. These results demonstrate the potential for significantly reducing dosing frequency through the combination of circular RNA and the novel LNP.
Professor Hiroshi Abe of Nagoya University stated, "This enables mRNA therapeutics that sustain their effects with smaller amounts of active ingredient. It also contributes to reducing side effects."
Broad Therapeutic Potential and Remaining Challenges
The technology developed in this study is expected to have broad applications, including cancer vaccines, genome editing, and replacement therapy for hereditary diseases caused by specific protein deficiencies. Its significance as a highly versatile delivery platform capable of carrying different types of RNA is also substantial.
That said, a long road remains from animal studies to clinical application. This research has demonstrated the important principle that "more durable circular RNA can be delivered safely and efficiently into cells," but further validation of safety and efficacy through preclinical studies and clinical trials will be necessary.
Conventional mRNA drugs have short durations of effect, requiring patients to receive repeated doses. By combining the long-term expression capability of circular RNA with high-efficiency delivery via the novel LNP, this achievement represents an important step toward next-generation RNA therapeutics that "sustain their effects over long periods with a single administration."