About the project

Therapeutic treatments based on the production of proteins by delivering messenger RNA (mRNA) represent a promising approach to treating many diseases that currently lack other alternatives. However, one of the major challenges is to protect these macromolecules from enzymatic degradation and deliver them to the target cells. Lipid nanoparticles (LNPs) formed by a cationic ionisable lipid (CIL), DSPC, cholesterol (Chol) and a pegylated (PEG) lipid have been approved by FDA for delivery of small interference RNA (siRNA) for the treatment of peripheral nerve disease. Nevertheless, there are still concerns about these nanoparticles' safety profile.

A good understanding of the physical and chemical characteristics of the LNPs under study is necessary to progress from pre-clinical testing. In addition, the biodistribution and cellular uptake of LNPs are affected by their surface composition as well as by the extracellular proteins present at the site of LNPs administration, such as proteins in the plasma. Therefore, it is also important to understand the relation between LNP physical-chemical properties and their ability to collect proteins from the plasma.

A common component found in the “protein corona” of LNPs is Apolipoprotein E (ApoE), which is responsible for the transport of fats in the systemic circulation and it triggers the fat uptake by cell-rich in low-density lipoprotein (LDL) receptors. This recognition step is critical to controlling the LNP’s circulation time and thus its pharmacological efficiency.

This project aims to understand how LNP composition and structure contribute to the LNP’s protein binding capacity and to unravel how LNP are taken up by cells, which is key to designing LNPs that can selectively target organs.

Affiliated: Marianna Yanez Arteta, Astra Zeneca AB and Lennart Lindfors, Astra Zeneca AB.