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J Control Release. 2014 Dec 28;196:28-36. doi: 10.1016/j.jconrel.2014.09.016. Epub 2014 Sep 20.

Efficient intracellular delivery and multiple-target gene silencing triggered by tripodal RNA based nanoparticles: a promising approach in liver-specific RNAi delivery.

Author information

1
Global Research Laboratory for RNAi Medicine, Department of Chemistry, Sungkyunkwan University, Suwon 440-746, Korea.
2
Department of Chemistry, Sungkyunkwan University, Suwon 440-746, Korea.
3
Department of Medical Biotechnology, Dongguk University, Seoul 100-715, Korea.
4
BMT Inc., Seoul, 153-777, Korea.
5
Skip Ackerman Center for Molecular Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
6
Global Research Laboratory for RNAi Medicine, Department of Chemistry, Sungkyunkwan University, Suwon 440-746, Korea. Electronic address: dklee@skku.edu.

Abstract

RNA interference (RNAi) triggering oligonucleotides in unconventional structural format can offer advantages over conventional small interfering RNA (siRNA), enhanced cellular delivery and improved target gene silencing. With this concept, we present a well-defined tripodal-interfering RNA (tiRNA) structure that can induce simultaneous silencing of multiple target genes with improved potency. The tiRNA structure, formed by the complementary association of three single-stranded RNA units, was optimized for improved gene silencing efficacy. When combined with cationic polymers such as linear polyethyleneimine (PEI), tiRNA assembled to form a stable nano-structured complex through electrostatic interactions and induced stronger RNAi response over conventional siRNA-PEI complex. In combination with a liver-targeting delivery system, tripodal nucleic acid structure demonstrated enhanced fluorescent accumulation in mouse liver compared to standard duplex nucleic acid format. Tripodal RNA structure complexed with galactose-modified PEI could generate effective RNAi-mediated gene silencing effect on experimental mice models. Our studies demonstrate that optimized tiRNA structural format with appropriate polymeric carriers have immense potential to become an RNAi-based platform suitable for multi-target gene silencing.

KEYWORDS:

Liver targeting; Nanoparticles; Polyethyleneimine; RNA interference; Tripodal-interfering RNA (tiRNA)

PMID:
25251899
DOI:
10.1016/j.jconrel.2014.09.016
[Indexed for MEDLINE]

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