A branching lipid efficiently transports messenger RNA

Messenger RNA (mRNA) is a biomolecule that transfers information encoded by genes in the nucleus into the cytoplasm to synthesize proteins
through ribosomes.
Messenger RNA sequences can be used to encode specific proteins; The best-known example is the mRNA vaccine
for COVID-19.
Messenger RNA molecules are large and chemically unstable, so carriers must be utilized to transport messenger RNA to cells
.
Lipid nanoparticles (LNPs) are one of the most advanced technologies for messenger RNA delivery and consist of
ionizable lipids, cholesterol, accessory lipids, and polyethylene glycol.

A research team led by Professor Yusuke Sato and Professor Hideyoshi Harashima, assistant professors at Hokkaido University's Faculty of Pharmacy, and Kazuki Hashiba, Nitto Electric Power Co.
, Ltd.
, developed a novel branching ionized lipid that, when contained in LNPs, greatly improves the delivery efficiency
of mRNA.

Previous studies have shown that ionizable lipids with branched tails can improve mRNA delivery efficiency
through lnp.
However, there are two major problems that impede systematic analysis
of the effects of branchable ionizable lipids.
First, the tail branch leads to a huge diversity of chemicals; Secondly, the number of branching ionized lipids available on the market is limited
.
To overcome these obstacles, the researchers generated a systematic lipid library of branching ionizable lipids and limited the library to a specific subset of branchable lipids that can be described by two parameters: total carbon number and symmetry
.
They then tested the effect
of 32 lipids in this library on the stability of LNPs containing mRNA (LNP-RNA).

The team found that LNP-RNA containing highly symmetrical branched-chain lipids exhibited greater microviscosity, while higher microviscosity was positively correlated
with increased stability of LNP-RNA in storage.
Highly symmetrical branched lipids in LNP-RNA were also positively correlated
with protein expression in mouse livers and spleens.
They determined that the length of the branched chain affects the selectivity
of the organ.

The most stable storage and the most efficient messenger RNA delivery is achieved by branching lipids CL4F 8-6
.
The authors demonstrated that this particular lipid could be used to design LNPs for gene editing, requiring only one dose of LNPs to achieve 77 percent of the target gene suppression
in mice.

The study shows that branching lipids with high symmetry contribute to efficient intracellular delivery of LNPs and stabilize the optimal properties of
the formulation.
Future work will focus on developing expanded lipid libraries to understand the properties of other branching lipids and potentially lead to the design of new lipids
.