Lectures and seminars Lipid nanoparticles for mRNA delivery: Using neutron scattering for successful redesign

12-12-2022 2:00 pm Add to iCal
Campus Solna Petrénsalen, Karolinska Institutet, Nobels väg 12B, Solna

This is the second seminar in a series organised by the Xrays and Neutrons for Biomedical Applications Network at Karolinska Institutet. Have a fika with us and hear Dr. Marianna Yanez Arteta from AstraZeneca talk about how to use small angle neutron scattering to invesitage the structure of lipid nanoparticles for mRNA delivery.

Abstract

The use of messenger RNA (mRNA) as a therapeutic treatment to produce a deficient protein in situ became a reality in 2020: 2 mRNA-based vaccines against SARS-CoV-2, produced by Pfizer/BioNTech and Moderna, received emergency authorization by multiple regulatory agencies around the world. The technology that made this possible was a lipid nanoparticle (LNP) used as a delivery vehicle that was originally designed for small interference RNA.

These LNPs are mainly composed by a cationic ionizable lipid, which is responsible of encapsulating and facilitating release into the cell cytosol, and helper lipids to provide stability to the particle such as cholesterol, a phospholipid and a poly(ethylene glycol) lipid. Despite the great advances in LNP development, there are still challenges to overcome relating to their efficacy, which is typically in the single digit percentage, as well as ensuring their safety.

Our work shows how a fruitful collaboration between industry, academia and neutron research facilities helped us to elucidate the structure of mRNA-containing LNPs in order to guide their rational design towards an improvement in their efficacy. We have found that both cholesterol and the phospholipid DSPC are enriched at the LNP surface, giving them a core-shell profile. These results allowed us to variate the LNP size and surface composition in order to increase intracellular protein production of up to 50-folds for certain LNPs in 2 different types of clinically relevant cells, human adipocytes and hepatocytes. This improvement is most likely related to the ability of LNPs to fuse with early endosome membranes1.

Additionally, we have used neutron scattering to investigate the fate of mRNA-containing LNPs in the presence of proteins2 and also to characterize LNPs containing non-steroidal anti-inflammatory drugs (NSAIDs)3. The fundamental understanding gained from probing the structure of mRNA-containing LNPs with techniques as neutron scattering provides insight into the mechanisms leading to LNP effectivity and will improve the possibility of success of mRNA therapies.

References

  1. Yanez Arteta, M.; Kjellman, T.; Bartesaghi, S.; Wallin, S.; Wu, X.; Kvist, A. J.; Dabkowska, A.; Székely, N.; Radulescu, A.; Bergenholtz, J.; Lindfors, L. PNAS 2018, E3351-E3360.
  2. Sebastiani, F.; Yanez Arteta, M.; Lerche, M.; Porcar, L.; Bragg, R.A..; Lang, C.; Elmore, C. S.; Krishnamurthy, V. R.; Russell, R.A; Darwish, T.; Pichler, H.; Waldie, S.; Moulin, M.; Haertlein, M.; Forsyth, V.T.; Lindfors, L. and Cárdenas, M. ACS Nano 2021, 15, 6709–6722
  3. Davies, N.; Hovdal, D.; Edmunds, N.; Nordberg, P.; Dahlén, A.; Dabkowska, A.; Yanez Arteta, M.; Radulescu, A.; Kjellman, T.; Höijer, A.; Seeliger, F.; Holmedal, E.; Andihn, E.; Bergenhem, N.; Sandinge, A.-S.; Johansson, C.; Hultin, L.; Johansson, M.; Lindqvist, J.; Björsson, L.; Jing, Y.; Bartesaghi, S.; Lindfors, L.; Andersson, S. Mol Ther – Nucleic Acids 2021, 24, 369-384.
Portrait of Marianna Yanez Arteta
Dr Marianna Yanez Arteta, AstraZeneca Photo: N/A

About Marianna Yanez Arteta

Marianna Yanez Arteta, Ph.D., is an Associate Director at the Advanced Drug Delivery division within Pharmaceutical Sciences in AstraZeneca. She did her PhD at Lund University, where she employed neutron reflectometry to understand the interactions between polymers and surfactants at interfaces. Thereafter, she was a postdoctoral researcher at AstraZeneca where she brought small angle neutron scattering expertise to investigate the structure of lipid nanoparticles for mRNA delivery.

In her current position she leads the team developing new modalities pharmaceutics in pre-clinical and early clinical phases, including mRNA, antisense oligonucleotides and peptides. As part of her role, she has guided the development of nanomedicines for complex therapeutics from the understanding of the molecular interactions in the formulation. 

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