Small Angle Neutron Scattering revels the distribution of lipidic components in Lipid based nanoparticles, and how this is affected by serum protein binding


Lipid based Nanoparticles (LNPs) constitute a potent nanotechnology used in drug and gene delivery. Indeed, the Covid19 vaccines by Pziffer and Moderna use this technology. LNP efficiency, however, is low (as determined by the protein expression capacity per loaded RNA) and efforts are continuously being made to increase their potency. For example, improving the uptake by the cells into the cytosol is necessary. Current formulations tend to accumulate in the liver, which is believed to be mediated by Apolipoprotein E (ApoE) binding from serum: ApoE bound to LNPs favours the uptake in liver cells mediated by the LDL receptors. Thus, understanding what triggers ApoE binding to LNPs and what this binding has for effect on LNP structure might help improving LNP efficiency.


The distribution of the lipidic components in LNPs was investigated by means of Small Angle Neutron Scattering (SANS) and selective isotopic substitution. This enabled the description of not only the overall LNP structure but also how the components are distributed. In the cellular uptake of LNPs, Apolipoprotein E (ApoE) is known to play a key role and it is known that ApoE is very abundant in the protein corona of LNPs. By incubating ApoE with shell-core contrast matched LNPs and with a range of deuteration schemes, SANS allowed the determination of the component redistribution within LNP core and shell where the shell suffers an enrichment in cholesterol with time.


Figure 1: ApoE binding induces a change of the SANS signal suggesting redistribution of the internal components.

What´s next?

By manipulating the surface composition of LNPs it may be possible to regulate ApoE3 binding. SANS and selective deuteration show the exact surface composition and how it evolves with time upon serum protein binding.


In a KK funded project, the Department of Biomedical Sciences at Malmö University in collaboration with AstraZeneca AB led this project with contributions from the Life Sciences Group at the ILL, the deuteration group at ANSTO, the Institute of Molecular Biotechnology at Graz University of Technology. Experiments were performed at ILL and FRM2.


Prof. Marité Cárdenas, Malmö University

Dr. Federica Sebastiani, Malmö University