Abstract

Lipid nanoparticles (LNPs) are the lead delivery system for nucleic acid therapeutics, such as siRNA, antisense oligonucleotides, and mRNA. Following nanoparticles systemic administration, a corona of biomolecules forms around them. The corona composition might be affected by disease and in consequence diminish therapeutic performance of nanoparticles. The relationship between LNPs composition, their delivery efficacy, and the biocoronas that form around LNPs is still poorly understood.Using an unbiased screening workflow, we have identified distinct protein corona components ensuring a very efficient LNPs uptake by liver cells. LNPs were first complexed with plasma samples from lean or obese rats and then their functionally was evaluated in a set of in vitro assays. A novel, automated, and miniaturized method was then employed to retrieve the LNPs with intact biocoronas. The analysis has revealed that high-density lipoproteins can interact with various types of LNPs and that augmenting LNP coronas with HDL improved their performance both in vitro and in vivo. Importantly, we have shown that the HDL corona signature was a superior predictor of LNPs in vivo activity as compared to the commonly used corona-biomarker Apolipoprotein E. Our results have revealed this previously unreported role of HDL forming a framework for improving LNP therapeutic efficacy by controlling corona composition.