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Image-based analysis of lipid nanoparticle-mediated siRNA delivery, intracellular trafficking and endosomal escape.

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Gilleron,  Jerome
Max Planck Institute of Molecular Cell Biology and Genetics, Max Planck Society;

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Zeigerer,  Anja
Max Planck Institute of Molecular Cell Biology and Genetics, Max Planck Society;

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Marsico,  Giovanni
Max Planck Institute of Molecular Cell Biology and Genetics, Max Planck Society;

/persons/resource/persons219652

Schubert,  Undine
Max Planck Institute of Molecular Cell Biology and Genetics, Max Planck Society;

/persons/resource/persons219424

Manygoats,  Kevin
Max Planck Institute of Molecular Cell Biology and Genetics, Max Planck Society;

/persons/resource/persons219662

Seifert,  Sarah
Max Planck Institute of Molecular Cell Biology and Genetics, Max Planck Society;

/persons/resource/persons218971

Andree,  Cordula
Max Planck Institute of Molecular Cell Biology and Genetics, Max Planck Society;

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Stöter,  Martin
Max Planck Institute of Molecular Cell Biology and Genetics, Max Planck Society;

/persons/resource/persons219150

Fava,  Eugenio
Max Planck Institute of Molecular Cell Biology and Genetics, Max Planck Society;

/persons/resource/persons219009

Bickle,  Marc
Max Planck Institute of Molecular Cell Biology and Genetics, Max Planck Society;

/persons/resource/persons219285

Kalaidzidis,  Yannis
Max Planck Institute of Molecular Cell Biology and Genetics, Max Planck Society;

/persons/resource/persons219807

Zerial,  Marino
Max Planck Institute of Molecular Cell Biology and Genetics, Max Planck Society;

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Citation

Gilleron, J., Querbes, W., Zeigerer, A., Borodovsky, A., Marsico, G., Schubert, U., et al. (2013). Image-based analysis of lipid nanoparticle-mediated siRNA delivery, intracellular trafficking and endosomal escape. Nature biotechnology, 31(7), 638-646.


Cite as: http://hdl.handle.net/21.11116/0000-0001-06EC-F
Abstract
Delivery of short interfering RNAs (siRNAs) remains a key challenge in the development of RNA interference (RNAi) therapeutics. A better understanding of the mechanisms of siRNA cellular uptake, intracellular transport and endosomal release could critically contribute to the improvement of delivery methods. Here we monitored the uptake of lipid nanoparticles (LNPs) loaded with traceable siRNAs in different cell types in vitro and in mouse liver by quantitative fluorescence imaging and electron microscopy. We found that LNPs enter cells by both constitutive and inducible pathways in a cell type-specific manner using clathrin-mediated endocytosis as well as macropinocytosis. By directly detecting colloidal-gold particles conjugated to siRNAs, we estimated that escape of siRNAs from endosomes into the cytosol occurs at low efficiency (1-2%) and only during a limited window of time when the LNPs reside in a specific compartment sharing early and late endosomal characteristics. Our results provide insights into LNP-mediated siRNA delivery that can guide development of the next generation of delivery systems for RNAi therapeutics.