Science1 publisher3 min readPublished
A capped circular RNA and a branched lipid particle take aim at the dosing schedule
Nagoya University and FUJIFILM report longer-lasting expression from capped circular RNA in a new lipid nanoparticle. The mouse data are directional; the duration numbers are not public yet.
The Scientist · Science desk
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What happened
- Researchers at Nagoya University in Japan, in collaboration with FUJIFILM, developed a novel way of delivering circular RNA (cirRNA) into cells; the research is published in Cell Biomaterials.
- Linear mRNA strands carry a cap end and a tail end which guide ribosomes to initiate translation, but degradation enzymes within the cell use the same terminal points to attack and break down the mRNA.
- cirRNA, being a loop, has no start or endpoint and is thus more resistant to degradation; without a specific stop marker, ribosomes can keep riding the loop to code for proteins, making cirRNA capable of driving gene expression for longer periods.
- cirRNA relies on internal instructions within its loop for gene translation, so its gene expression efficacy can be lower compared with mRNA's cap and end marker system.
- Hiroshi Abe, Seigo Kimura and their team at Nagoya University's Integrated Research Consortium on Chemical Sciences (IRCCS) and the Department of Chemistry made a cirRNA with a cap end, called Cap-cirRNA.
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Why it matters
Researchers at Nagoya University, working with FUJIFILM, say they have delivered a capped circular RNA into cells using a purpose-built lipid nanoparticle, with the work published in Cell Biomaterials [1]. The interesting variable here is not the chemistry but the clock: expression duration sets injection frequency, and injection frequency sets the cost and the adherence profile of anything from an mRNA cancer vaccine to an RNA-encoded GLP-1.
The mechanism is straightforward. A linear mRNA's cap and tail recruit ribosomes, but those same ends are where degradation enzymes get a grip [2]. A loop has no ends, so it resists that attack, and without a stop marker ribosomes can keep circling and producing protein [3]. The trade is translation efficiency: circular RNA depends on internal initiation instructions, which the researchers describe as less effective than the cap-and-tail system [4]. The Nagoya group, led by Hiroshi Abe and Seigo Kimura at the university's Integrated Research Consortium on Chemical Sciences and the Department of Chemistry, built a circular RNA that carries a cap anyway [5]. Abe says Cap-cirRNA "combines the strengths of mRNA and cirRNA to provide durability and efficient (gene) translation for a longer time" [6].
The carrier came from outside the university. FL0445-LNP was obtained from FUJIFILM's Bioscience and Engineering Laboratories [7]. Its distinguishing feature is branched biodegradable lipid chains where conventional particles use linear ones, which the team reports gives enough internal flexibility to carry nucleic acids of varying weight and structure [8]. They also report a tenfold increase in mRNA activity with negligible inflammatory response relative to conventional LNPs [9]. That figure is for mRNA, not for Cap-cirRNA, and the release does not define the comparator particle.
For the in vivo test the team chose GLP-1, the peptide behind Ozempic and Wegovy, which today is administered by subcutaneous injection [10]. Both linear mRNA and Cap-cirRNA encoding GLP-1 were administered in mice using FL0445-LNP; Cap-cirRNA showed higher functional activity, and the team says more work is needed to tune the process [11]. The stated commercial logic is longer treatment duration and fewer injections [12]. Kimura, the study's lead author, frames the platform argument: once there is a common way to safely deliver stronger or more durable mRNA, more applications open up [13].
What the coverage does not contain is the number that would let an operator model any of this. There is no reported half-life, no expression curve, no dose interval, and no circulating protein concentration for either construct [14]. "Longer" and "higher functional activity" are directions, not quantities, and a mouse dosing interval does not translate to a human one. Abe also lists cancer vaccines, genome editing and protein supplementation for genetic disorders as targets [15], which is the standard list for any nucleic acid delivery platform and should be read as scope rather than progress.
Three things to watch. First, the actual figures in the Cell Biomaterials paper, titled "A Branched Ionizable Lipid Nanoparticle Platform for Versatile In Vivo Delivery of Nucleic Acids" [16], and specifically whether the durability advantage is measured in days or weeks. Second, whether the tenfold activity gain and the low inflammatory signal hold when the cargo is a capped circle rather than linear mRNA [9]. Third, the commercial posture: FL0445-LNP is corporate material supplied to an academic group [7], and whether FUJIFILM makes it broadly available will determine whether this is a platform or a single collaboration.