Structure-guided design of endosomolytic chloroquine-like lipid nanoparticles for mRNA delivery and genome editing

Zhen Liu, Jiacai Wu, Ning Wang, Yongqi Lin, Ruiteng Song, Min Zhang and Bin Li ()
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Zhen Liu: Jinan University
Jiacai Wu: Southern University of Science and Technology
Ning Wang: Southern University of Science and Technology
Yongqi Lin: Southern University of Science and Technology
Ruiteng Song: Jinan University
Min Zhang: Jinan University
Bin Li: Jinan University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Despite remarkable progress in designing RNA delivery systems, endosomal escape remains a recognized challenge for efficient RNA delivery. In this study, we develop a robust mRNA delivery platform termed endosomolytic chloroquine-like optimized lipid nanoparticles (ecoLNPs) for versatile mRNA delivery in vitro and in vivo via integrating the signature scaffold extracted from endosomolytic chloroquine into ionizable lipids. RNase-resistant ecoLNPs are capable of delivering a broad variety of mRNA payloads to diverse cell types, even hard-to-transfect 3D cells, with an efficiency of up to 18.9-fold higher than that of commercial transfection reagents. The pH-responsive endosomolytic activity of ecoLNPs can be largely attributed to the proton sponge effect and saposin B-promoted membrane disruption. In vivo, ecoLNPs enable potent local and systemic mRNA delivery and exhibit comparable potency to the clinically approved mRNA vaccine carrier, but strong tropism for lymph nodes following intramuscular injection. Furthermore, ecoLNPs are able to retain in vivo delivery potency for at least one week under non-frozen conditions and induce efficient genome editing in transgenic mice. Overall, the structure-guided integration strategy provides a pathway for de novo design of endosomolytic mRNA delivery systems.

Date: 2025
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DOI: 10.1038/s41467-025-59501-y

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