A novel class of zwitterionic phospholipids promotes mRNA delivery

A new study conducted by researchers at Hokkaido University has announced a new class of zwitterionic phospholipids that can significantly enhance the functional delivery of mRNAs. This study was published in Advanced Science.

The new phospholipid, dope CX, was derived from a compound called dope, which is itself a phospholipid. Phospholipids are an important component of the cell membrane and are used to create lipid nanoparticles (LNPs) for targeted drug delivery.

DOPE-CX can form a special structure called a “cubic phase.” This helps overcome the major challenges of mRNA delivery by LNPS:endosomal escape. LNPs are harvested in cells in the form of endosomes, and escape from these endosomes (endosomal escapes) is an important hurdle that limits the effectiveness of mRNA therapy.

A study led by Associate Professor Sato Sato of the Faculty of Pharmaceutical Sciences at Hokkaido University shows that doped CX lipids with specific hydrophobic chain structures induce non-paralytic cubic phases when mixed with phosphatidylcholine (PC). This unique property promotes endosome escape via membrane fusion, improving liver mRNA expression compared to traditional phospholipids such as DSPCs and doping.

“Endosomal escapes are one of the most important challenges in RNA delivery, and are often less than 10% efficient,” explains Sato. “Our research highlights the possibility of reasonably engineered phospholipids like Dope-CX to overcome this limitation and enhance the therapeutic use of mRNA.”

Certain DOPE-CX derivatives, such as DOPE-C8, showed significantly higher levels of liver mRNA expression. These lipids were rapidly eliminated from liver tissue, reducing long-term accumulation and toxicity concerns. Engineered functionalized phospholipids have high hopes for the development of lipid nanoparticles (LNPs) used in mRNA vaccines, cancer treatments, protein replacement therapy, and more.

In particular, the derivative DOPE-C8 demonstrated the highest efficiency, promoting endosome escape and protecting mRNA from blood flow degradation. It was also rapidly removed from the liver, minimizing the risk of toxicity. However, these findings are limited to mice and further research is needed to confirm their applicability to humans and other animals.

“This study not only advances understanding of lipid-based delivery systems, but also opens up new measures for the rational design of functionalized phospholipids,” adds Professor Hisoshi Harashima, co-author of the study.

Although the current study focuses on liver-specific mRNA delivery, the team plans to investigate the broader applicability of doped CX lipids across different tissues and routes of administration. Further investigation of the detailed mechanisms of membrane fusion and spatio-temporal interactions will guide the development of next-generation LNPs.