Kidney-Targeted Cytosolic Delivery of siRNA Using a Small-Sized Mirror DNA Tetrahedron for Enhanced Potency

Hien Bao Dieu Thai; Kyoung Ran Kim; Kyung Tae Hong; Taras Voitsitskyi; Jun Seok Lee; Chengde Mao; Dae Ro Ahn

doi:10.1021/acscentsci.0c00763

Kidney-Targeted Cytosolic Delivery of siRNA Using a Small-Sized Mirror DNA Tetrahedron for Enhanced Potency

Hien Bao Dieu Thai, Kyoung Ran Kim, Kyung Tae Hong, Taras Voitsitskyi, Jun Seok Lee, Chengde Mao, Dae Ro Ahn

Research output: Contribution to journal › Article › peer-review

20 Citations (Scopus)

Abstract

A proper intracellular delivery method with target tissue specificity is critical to utilize the full potential of therapeutic molecules including siRNAs while minimizing their side effects. Herein, we prepare four small-sized DNA tetrahedrons (sTds) by self-assembly of different sugar backbone-modified oligonucleotides and screened them to develop a platform for kidney-targeted cytosolic delivery of siRNA. An in vivo biodistribution study revealed the kidney-specific accumulation of mirror DNA tetrahedron (L-sTd). Low opsonization of L-sTd in serum appeared to avoid liver clearance and keep its size small enough to be filtered through the glomerular basement membrane (GBM). After GBM filtration, L-sTd could be delivered into tubular cells by endocytosis. The kidney preference and the tubular cell uptake property of the mirror DNA nanostructure could be successfully harnessed for kidney-targeted intracellular delivery of p53 siRNA to treat acute kidney injury (AKI) in mice. Therefore, L-sTd could be a promising platform for kidney-targeted cytosolic delivery of siRNA to treat renal diseases.

Original language	English
Pages (from-to)	2250-2258
Number of pages	9
Journal	ACS Central Science
Volume	6
Issue number	12
DOIs	https://doi.org/10.1021/acscentsci.0c00763
Publication status	Published - 2020 Dec 23
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Chemical Engineering(all)

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title = "Kidney-Targeted Cytosolic Delivery of siRNA Using a Small-Sized Mirror DNA Tetrahedron for Enhanced Potency",

abstract = "A proper intracellular delivery method with target tissue specificity is critical to utilize the full potential of therapeutic molecules including siRNAs while minimizing their side effects. Herein, we prepare four small-sized DNA tetrahedrons (sTds) by self-assembly of different sugar backbone-modified oligonucleotides and screened them to develop a platform for kidney-targeted cytosolic delivery of siRNA. An in vivo biodistribution study revealed the kidney-specific accumulation of mirror DNA tetrahedron (L-sTd). Low opsonization of L-sTd in serum appeared to avoid liver clearance and keep its size small enough to be filtered through the glomerular basement membrane (GBM). After GBM filtration, L-sTd could be delivered into tubular cells by endocytosis. The kidney preference and the tubular cell uptake property of the mirror DNA nanostructure could be successfully harnessed for kidney-targeted intracellular delivery of p53 siRNA to treat acute kidney injury (AKI) in mice. Therefore, L-sTd could be a promising platform for kidney-targeted cytosolic delivery of siRNA to treat renal diseases.",

author = "Thai, {Hien Bao Dieu} and Kim, {Kyoung Ran} and Hong, {Kyung Tae} and Taras Voitsitskyi and Lee, {Jun Seok} and Chengde Mao and Ahn, {Dae Ro}",

note = "Funding Information: This study was supported by intramural grants of KIST, the Pioneer Research Center Program (2014M3C1A3054141) and National Research Foundation of Korea grant funded by the Korea government (MSIT) (2020R1A2C2008213). It was also supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF funded by the Korean government (MSIT) (2020M3E5E2037598). Publisher Copyright: {\textcopyright} 2020 American Chemical Society.",

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AU - Thai, Hien Bao Dieu

AU - Kim, Kyoung Ran

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AU - Voitsitskyi, Taras

AU - Lee, Jun Seok

AU - Mao, Chengde

AU - Ahn, Dae Ro

N1 - Funding Information: This study was supported by intramural grants of KIST, the Pioneer Research Center Program (2014M3C1A3054141) and National Research Foundation of Korea grant funded by the Korea government (MSIT) (2020R1A2C2008213). It was also supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF funded by the Korean government (MSIT) (2020M3E5E2037598). Publisher Copyright: © 2020 American Chemical Society.

PY - 2020/12/23

Y1 - 2020/12/23

N2 - A proper intracellular delivery method with target tissue specificity is critical to utilize the full potential of therapeutic molecules including siRNAs while minimizing their side effects. Herein, we prepare four small-sized DNA tetrahedrons (sTds) by self-assembly of different sugar backbone-modified oligonucleotides and screened them to develop a platform for kidney-targeted cytosolic delivery of siRNA. An in vivo biodistribution study revealed the kidney-specific accumulation of mirror DNA tetrahedron (L-sTd). Low opsonization of L-sTd in serum appeared to avoid liver clearance and keep its size small enough to be filtered through the glomerular basement membrane (GBM). After GBM filtration, L-sTd could be delivered into tubular cells by endocytosis. The kidney preference and the tubular cell uptake property of the mirror DNA nanostructure could be successfully harnessed for kidney-targeted intracellular delivery of p53 siRNA to treat acute kidney injury (AKI) in mice. Therefore, L-sTd could be a promising platform for kidney-targeted cytosolic delivery of siRNA to treat renal diseases.

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Kidney-Targeted Cytosolic Delivery of siRNA Using a Small-Sized Mirror DNA Tetrahedron for Enhanced Potency

Abstract

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