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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-08

AUTHORS

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

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. More... »

PAGES

870-876

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nbt.3298

DOI

http://dx.doi.org/10.1038/nbt.3298

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1042680450

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/26192320


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