Lipid nanoparticle stereochemistry shapes mRNA delivery safety and efficacy, study reveals

A team from the Max-Planck-Assitut Für Kohlenforschung, Hokkaido University and Osaka University has discovered that subtle differences in the molecular structure can have a major impact on the performance of mRNA drugs. Their results, published in the Journal of the American Chemical SocietyOpen the door to the development of safer and more effective vaccines and therapies.

To deliver therapeutic nucleic acids such as mRNA in cells, scientists rely on lipid nanoparticles (LNP) – fat bearers who protect a fragile genetic material, which allows it to survive in the body and reach target cells. A key component of these LNPs is ionizable lipids, which help the mRNA to enter the cells, then to release it effectively. One of these lipids, ALC-315, was used in particular in the Pfizer / Biontech COVVI-19 vaccine, a medical breakthrough that played an essential role in controlling the world pandemic.

The neglected impact of stereochemistry

Although the vaccine is safe and very effective, a surprising detail has remained largely unnoticed: ALC -315 is used as a mixture of three stereoisomers – molecules which have the same chemical formula but differ in their three -dimensional arrangement, a bit like left and right hands. This distinction is not trivial. It is well known that stereoisomers can behave very differently in biological systems, affecting how drugs are absorbed, distributed and metabolized.

Until now, the three isomers of ALC-315, (S, S), (R, R) and MESO, had never been studied individually in the context of the performance of the LNP. In their study, Dr. Chandra Kanta of Max-Planck-Aistit Für Kohlenforschung and his colleagues synthesized and tested each pure stereoisomer for the first time.

“We demonstrate that stereochemistry has a direct impact on LNP efficiency and safety”, explains Dr. de. “In particular, we have found that the form (s, s) delivers the mRNA just as effectively as the standard mixture, but with significantly reduced toxicity.”

Dr. Masumi Tsuda of Hokkaido University in Japan, who carried out the biological analysis of the ALC-315 isomers with Professor Shinya Tanaka, said: “We would be delighted if these research results could contribute to the development of safer vaccines.”

These results are very relevant because LNP technology is developing rapidly beyond COVVI-19 vaccines, with applications ranging from gene therapy to personalized cancer vaccines. While the field grows towards the next generation of therapies based on mRNA, the need for precise and optimized components is becoming more and more important. The study opens the way to improved LNP formulations, offering the potential of a safer and more efficient mRNA delivery in a wide range of future therapies.