Cited by 693RNA Interference and Gene DeliveryNanoparticle-Based Drug DeliveryCellular transport and secretion

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Visualizing lipid-formulated siRNA release from endosomes and target gene knockdown

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Wittrup, Anders, Ai, Angela, Liu, Xing, Hamar, Peter, Trifonova, Radiana, Charisse, Klaus, Manoharan, Muthiah, Kirchhausen, Tomas, Lieberman, Judy·2015·Nature Biotechnology

DOI 10.1038/nbt.3298PMC PMC4663660

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Abstract

A central hurdle in developing small interfering RNAs (siRNAs) as therapeutics is the inefficiency of their delivery across the plasma and endosomal membranes to the cytosol, where they interact with the RNA interference machinery. With the aim of improving endosomal release, a poorly understood and inefficient process, we studied the uptake and cytosolic release of siRNAs, formulated in lipoplexes or lipid nanoparticles, by live-cell imaging and correlated it with knockdown of a target GFP reporter. siRNA release occurred invariably from maturing endosomes within ~5-15 min of endocytosis. Cytosolic galectins immediately recognized the damaged endosome and targeted it for autophagy. However, inhibiting autophagy did not enhance cytosolic siRNA release. Gene knockdown occurred within a few hours of release and required <2,000 copies of cytosolic siRNAs. The ability to detect cytosolic release of siRNAs and understand how it is regulated will facilitate the development of rational strategies for improving the cytosolic delivery of candidate drugs.

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Authors: Wittrup, A., Ai, A., Liu, X., Hamar, P., Trifonova, R., Charisse, K., Manoharan, M., Kirchhausen, T., & Lieberman, J.
Affiliations: Boston Children's Hospital (US)
Alnylam Pharmaceuticals (United States) (US)
Corresponding author: Wittrup, Anders
Lieberman, Judy
ORCID: Wittrup, Anders
Ai, Angela
Liu, Xing
Hamar, Peter
Trifonova, Radiana
Manoharan, Muthiah
Kirchhausen, Tomas
Lieberman, Judy
Venue: Nature Biotechnology
Publisher: Springer Science and Business Media LLC
Published: 2015-07-20
Volume: 33
Issue: 8
Pages: 870-876
ISSN: 0733-222X (ISSN-L)
1087-0156
1546-1696
DOI: 10.1038/nbt.3298
PMC: PMC4663660
OpenAlex: W1844274376
Cited by: 693
References: 30
Citations by year: 2026: 101 · 2025: 104 · 2024: 82 · 2023: 60 · 2022: 59 · 2021: 63 · 2020: 53 · 2019: 40 · 2018: 54 · 2017: 37 · 2016: 31 · 2015: 8
FWCI: 18.70
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature Biotechnology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Lund University Publications (Lund University) (submittedVersion)
Funders: National Institutes of Health
National Cancer Institute (R01CA139444, CA139444)
National Institute of General Medical Sciences (GM075252, R01GM075252)
National Institute of Allergy and Infectious Diseases (AI090671, AI057159, R01AI090671, U54AI057159)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords: siRNA delivery, endosomal escape, lipoplexes, lipid nanoparticles, endocytosis, autophagy, galectins, gene knockdown, live-cell imaging, RNA interference, siRNA therapeutics
MeSH terms: HeLa Cells, Humans, Lipids, Luminescent Proteins, Endosomes, RNA Interference, RNA, Small Interfering, Nanoparticles, Gene Knockdown Techniques

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Visualizing lipid-formulated siRNA release from endosomes and target gene knockdown

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