New Delivery Vehicle Advances Next-Generation mRNA Therapeutics

Messenger RNA transformed vaccine science during the COVID-19 pandemic, but its success depended on a delivery system capable of protecting a fragile genetic molecule and transporting it into cells. Researchers at Nagoya University and FUJIFILM Corporation have now reported a lipid nanoparticle platform designed to carry both conventional linear mRNA and a more durable form of circular RNA. In experiments in mice, the system delivered genetic instructions for producing glucagon-like peptide-1, or GLP-1, a hormone increasingly associated with modern obesity treatments. The findings suggest that combining a flexible lipid nanoparticle with a specially engineered circular RNA could extend the duration and versatility of nucleic-acid medicines.

The new delivery vehicle, known as FL0445-LNP, belongs to a class of microscopic particles that function somewhat like molecular containers. Lipid nanoparticles are assembled from fat-like molecules that form a protective structure around nucleic acids. Their outer surfaces are compatible with the watery environment of the body, while their lipid composition helps them interact with cell membranes. After being taken up by cells, the particles are designed to break down and release their cargo. This process allows the delivered mRNA or circular RNA to reach the cellular machinery responsible for translating genetic instructions into proteins.

The need for such protection arises from the inherent instability of linear mRNA. A conventional messenger RNA molecule has defined ends, including a cap structure that helps ribosomes recognize it and a tail that contributes to stability and translation. These same terminal regions, however, can also become targets for cellular enzymes that degrade RNA. Once the molecule is destroyed, protein production stops. This limited lifetime is useful for some applications, including transient vaccination, but it can be a disadvantage when a therapeutic protein needs to be produced over a longer period.

Circular RNA, or cirRNA, offers a different molecular architecture. Instead of having two exposed ends, the RNA strand is joined into a continuous loop. This configuration removes the terminal points that many degradation enzymes attack, potentially allowing the molecule to remain active in cells for longer periods. Because circular RNA lacks a natural stop point, ribosomes may repeatedly move around the loop and generate multiple copies of the encoded protein. Yet the structure also introduces a challenge: circular RNA does not naturally possess the cap-and-tail arrangement that makes linear mRNA highly efficient at initiating translation.

To address this limitation, Hiroshi Abe, Seigo Kimura, and colleagues at Nagoya University’s Integrated Research Consortium on Chemical Sciences and Department of Chemistry developed a capped circular RNA construct called Cap-cirRNA. The design retains the closed-loop structure associated with increased resistance to degradation while adding a cap-related feature intended to improve the initiation of protein synthesis. The researchers describe the approach as an effort to combine the durability of circular RNA with the strong translation performance of conventional mRNA. In principle, this could allow cells to produce a therapeutic protein efficiently without requiring repeated administration of unstable RNA molecules.

The team paired Cap-cirRNA with FL0445-LNP, a nanoparticle obtained from researchers at the Bioscience & Engineering Laboratories of FUJIFILM Corporation. A notable feature of the particle is the branched biodegradable chains within its ionizable lipid component. Conventional lipid nanoparticles often rely on lipids with more linear structures. By introducing branching, the researchers sought to create a more flexible internal environment capable of accommodating nucleic acids with different sizes, weights, and molecular shapes. That flexibility may be particularly important for circular RNA, whose geometry and physical properties differ from those of linear mRNA.

In comparative experiments, FL0445-LNP increased mRNA activity by approximately tenfold relative to conventional lipid nanoparticle formulations, while producing a negligible inflammatory response under the reported conditions. The finding is significant because inflammation remains an important consideration in RNA medicine. Lipid nanoparticles must be sufficiently active to deliver their cargo, but excessive immune stimulation can limit dosing, reduce tolerability, or complicate repeated treatment. A biodegradable and adaptable particle that combines efficient delivery with a restrained inflammatory profile could therefore be useful across several classes of nucleic-acid therapies.

For an initial therapeutic test, the researchers selected GLP-1, a peptide hormone that helps regulate blood glucose and appetite. Current GLP-1 medicines, including drugs used in obesity treatment, generally deliver the peptide or a peptide analogue directly through injection. An RNA-based strategy takes a different route: rather than supplying the finished protein, it provides cells with the genetic instructions needed to manufacture it. If those instructions remain active for an extended period, the approach could potentially reduce the frequency of injections. In the mouse experiments, FL0445-LNP successfully delivered both linear mRNA and Cap-cirRNA encoding GLP-1 and produced measurable biological activity.

Cap-cirRNA showed greater functional activity than the corresponding linear mRNA in the animal studies, although the researchers emphasize that the system requires further optimization before its therapeutic potential can be assessed in humans. Important questions remain concerning dose, tissue distribution, duration of protein production, immune responses after repeated administration, and the control of circular RNA activity. The amount of protein produced must also be carefully regulated, since prolonged or excessive expression could create safety risks depending on the therapeutic target. Nevertheless, the results provide evidence that a branched ionizable lipid nanoparticle can serve as a common delivery platform for chemically and structurally distinct RNA cargos.

The researchers envision applications extending beyond GLP-1 therapy. The platform could support next-generation vaccines in which durable protein production improves immune training, as well as cancer vaccines designed to present tumor-associated antigens to the immune system. It may also be relevant to genome-editing technologies, which require the temporary delivery of messenger RNA and editing components into cells. In genetic disorders caused by missing or defective proteins, the same strategy might provide instructions for producing a functional replacement protein. By pairing a versatile nanoparticle with RNA molecules engineered for either rapid or prolonged activity, the work points toward a broader toolkit for protein replacement, vaccination, and other forms of precision medicine.

News Publication Date: 19-Aug-2026

Web References: Nagoya University Integrated Research Consortium on Chemical Sciences: https://irccs.nagoya-u.ac.jp/ ; Nagoya University Department of Chemistry: https://www.chem.nagoya-u.ac.jp/en/

References: Cell Biomaterials, “A Branched Ionizable Lipid Nanoparticle Platform for Versatile In Vivo Delivery of Nucleic Acids: Validation from mRNA to Capped Circular RNA,” published 19-Aug-2026.