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Predictive in vitro profiling of LNP-induced innate immune response using an iPSC-derived monocyte model

Xiao, B.; Kim, S.; Laufer, B.; Antonelli, A.; Hornhurg, M.; Murali, D.; Gu, Y.; Jessen, P.; Rigas, D.; Leylek, R.; Hokeness, K.; Freund, E.; Torres, E.; Ruggeri, G.; Tahtinen, S.; Fan, Y.; Yen, C.-W.; Emani, M. R.

2025-09-29 bioengineering
10.1101/2025.09.26.678842 bioRxiv
Show abstract

Lipid nanoparticles (LNPs) are a powerful drug delivery platform advancing vaccines and gene therapies. While their efficacy and safety has been found to be closely linked to innate immune activation, current in vitro models are unable to predict immune responses reliably. Conventional models, such as PBMCs, are limited by donor variability and inconsistent sensitivity. To address this, we developed a cytokine profiling platform using induced pluripotent stem cell (iPSC)-derived monocytes (iMonocytes), a physiologically relevant innate immune cell type that plays a key role in immune surveillance and inflammation. iPSCs provide a renewable, uniform monocyte source for consistent, high-sensitivity LNP screening. When tested with LNPs of graded immunostimulatory potency, iMonocytes showed improved reproducibility and strong correlation with in vivo cytokine responses. This platform enables evaluation of cargo- and dose-dependent effects, providing a robust and scalable tool for preclinical assessment and rational design of LNP therapeutics.

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