Interactions between mRNA lipid nanoparticles and immune cells in fresh human whole blood

Around 90 % of the drugs that enter clinical trials fail to reach the market. A main cause for this disturbing statistic is the poor correlation between drug performance in the clinic and in preclinical models of human (patho)physiology. Especially for drugs with complex structure-function relationships, such as mRNA lipid nanoparticles (mRNA-LNPs), this is problematic due to their very high dependency on large-scale preclinical screening approaches in their development. mRNA-LNPs and other nanomedicines are often administered systemically where they interact with plasma proteins and circulating cells, which strongly affects therapeutic applications. Moreover, in various nanotherapeutic strategies, circulating immune cells may be therapeutic targets. Human whole blood is successfully used ex vivo to study human immunity, disease trajectories, and drug performance and side effects. To assess human blood's utility in mRNA-LNP development, we here screened for interactions between mRNA-LNPs and 5 immune cell types in human whole blood. We demonstrated that with only 6 blood donors and a systematically designed mRNA-LNP mini-library, it is possible to identify significant effects of different lipid ingredients on mRNA-LNP cellular uptake and cytokine induction. Our findings suggest that ex vivo use of human blood may become a valuable addition to the mRNA-LNP preclinical development pipeline.