A research group based at Nagoya University has developed a specialized lipid nanoparticle called FL0445 that can deliver a wider range of RNA therapies to a target than other lipid nanoparticles.
The work, which is being developed in partnership with Fujifilm, is still at an early stage, but may provide a more flexible and better-tolerated way to get circular RNA and other genetic therapies into cells, an important requirement for RNA medicines designed to work for longer and be dosed on a regular basis.
“The success of mRNA vaccines has shown the transformative power of RNA medicines, and the field is now moving toward next-generation modalities such as circular RNA, which offers greater stability and more durable protein expression than linear mRNA,” wrote the investigators in Cell Biomaterials.
“A key hurdle is delivery: conventional lipid nanoparticles are optimized for linear mRNA and struggle with the rigid, closed-loop structure of circular RNA.”
Most standard lipid nanoparticles were created to fit and carry relatively flexible, linear mRNA, not circular RNA. FL0445 has three lipid branches around a central charged group. The authors propose that this branching prevents the lipids from packing too tightly, creating a less rigid internal structure. FL0445 also contains a helper lipid called DOPE (dioleoylphosphatidylethanolamine), which may help the RNA to escape into the target cell.
In this study, the researchers tested the efficacy of FL0445 at delivering a therapeutic load in human cell lines and in a mouse model. In this case, they used a glucagon-like peptide (GLP)-1 encoding circular RNA to treat obese mice with glucose intolerance.
FL0445 delivered a range of RNA types and sizes of molecules efficiently in cells, often more effectively than comparison formulations. It caused less activation of inflammatory pathways than other commonly used delivery particles and also seemed to use a different, cholesterol-dependent route than other methods, which may help it to reach its target better and avoid being targeted by the parts of the cell that break down unwanted material.
In mice, FL0445 was particularly effective after injection under the skin or into muscle. It also produced lower levels of inflammatory cytokines, including interleukin-6 and tumor necrosis factor-alpha, than some comparator particles.
“These data support our hypothesis that introducing a branched scaffold into the hydrophobic lipid tail generates a more flexible internal lipid nanoparticle architecture, enabling efficient accommodation of rigid payloads such as circular RNA while improving both delivery performance and safety,” the authors wrote.
However, they do acknowledge that more work is needed to develop this work further; the delivery mechanism remains partly unresolved, and repeated-dose safety, manufacturing, and performance in larger animals and people still need to be established.
