Therapeutic treatments based on the production of proteins by delivering messenger RNA (mRNA) represent a promising approach to treat many diseases that currently lack other alternatives. One of the major challenges for designing such treatments is the adequate protection of these macromolecules from enzymatic degradation and their safe deliver into the target cells. Lipid nanoparticles (LNPs) are promising vehicles for mRNA delivery and are formed by a cationic ionizable lipid (CIL), DSPC, cholesterol (Chol) and a pegylated (PEG) lipid. Even though some LNPs were recently FDA approved for the treatment of peripheral nerve disease by delivery of small interference RNA (<i>siRNA</i>), and vaccine against SARS-CoV-2 based on mRNA-LNPs have been developed and approved in the last months, there are still concerns about the safety profile of these nanoparticles. 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 bio-distribution 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. 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 control the LNP’s circulation time and thus its pharmacological efficiency.<br/>We employed small angle neutron scattering (SANS) to investigate the distribution of components in the LNP and the effect that ApoE could have on the LNP structure. In addition, we have developed a sensor platform based on Quartz Crystal Microbalance with Dissipation (QCM-D) to assess the binding affinity of serum protein to LNPs with different size and surface composition.<br/>Combining these approaches, we could determine how changes in the LNP formulation, and hence structure, affect the protein binding to LNPs.

Can mRNA - lipid nanoparticle surface composition regulates apolipoprotein binding from serum?

ACS Spring Meeting 2021

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