Saving lives by rerouting drug payloads
The concepts of 'drug payloads' and 'mRNA' have entered the everyday lexicon since the Covid-19 pandemic. Such therapeutic treatments have huge potential, but there is still a lot to be learned.
AstraZeneca is advancing the use of novel lipid nanoparticles (LNPs) — the carrier by which mRNAs are delivered to cells — to promote delivery of RNA-based therapeutics; it is working with Malmö University researcher Federica Sebastiani to further investigate their capabilities.
So literally, you have the potential to do whatever with this kind of platform, because the mRNA can be chosen to target whatever disease.
Understanding the composition and structure of LNPs, and their behaviour in the body is crucial to increase efficacy and broaden the scope of what they can be used to treat.
LPNs are very versatile, however, upon intravenously entering the body, various proteins bind to them; in addition, it is unknown what precisely happens to their internal composition, explains Sebastiani, who is based at the Biofilms Research Center for Biointerfaces.
They can be loaded with, for example, siRNAs or mRNAs, both of which influence the protein expression in the body in different ways. The siRNA drug patisiran, the focus of the study, has the same lipid composition as the technology utilised by some of the mRNA Covid-19 vaccines.
“There are differences, but the platform is the same. These technologies are extremely versatile. They teach our bodies how to react or to produce a protein that is needed in the body, or knockdown protein production to treat a disease.
“So literally, you have so much potential with this kind of platform, because the mRNA can be chosen to target whatever disease. The problem is that these particles go directly to the liver, and we would like to be able to target different organs — that will open a much wider range of diseases that we will be able to treat.”
The Knowledge Foundation funded research project, 'Lipid nanoparticles-protein interactions: How to tune the formulation and improve the therapeutic performance' utilised small-angle neutron scattering (SANS) and lab-based research methods for its findings.
The biodistribution and cellular uptake of LNPs are affected by the binding of ApoE and this seems to be tuned by the LNP surface composition. ApoE is responsible for fat transport in the body and plays a key role in the LNP’s circulation in the blood.
“Why does ApoE bind to LNPs, can we tune the LNP formulation to modify the surface structure and how it appears to the protein, making it less likely to bind and avoid accumulation in the liver so we can then target other organs?
“We wanted to understand if ApoE is only attaching to the particle or is it modifying the particle. And that is what we found, that it changes the component distribution, meaning it can affect its efficacy,“ says Sebastiani.
The small-angle neutron scattering was carried out in Germany (FRM-II) and France (ILL). However, Sebastiani was keen to stress the importance of such technology, highlighting the European Spallation Source (ESS), a future leading large-scale facility, which is currently under construction just outside of Lund.
“Without the use of neutron scattering it would not have been possible to carry out this research,” she adds.