Ultrastable synergistic tetravalent RNA nanoparticles for targeting to cancers

Farzin Haque; Dan Shu; Yi Shu; Luda S. Shlyakhtenko; Piotr G. Rychahou; B. Mark Evers; Peixuan Guo

doi:10.1016/j.nantod.2012.06.010

Ultrastable synergistic tetravalent RNA nanoparticles for targeting to cancers

Farzin Haque, Dan Shu, Yi Shu, Luda S. Shlyakhtenko, Piotr G. Rychahou, B. Mark Evers, Peixuan Guo

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

152 Scopus citations

Abstract

One of the advantages of nanotechnology is the feasibility to construct therapeutic particles carrying multiple therapeutics with defined structure and stoichiometry. The field of RNA nanotechnology is emerging. However, controlled assembly of stable RNA nanoparticles with multiple functionalities which retain their original role is challenging due to refolding after fusion. Herein, we report the construction of thermodynamically stable X-shaped RNA nanoparticles to carry four therapeutic RNA motifs by self-assembly of reengineered small RNA fragments. We proved that each arm of the four helices in the X-motif can harbor one siRNA, ribozyme, or aptamer without affecting the folding of the central pRNA-X core, and each daughter RNA molecule within the nanoparticle folds into their respective authentic structures and retains their biological and structural function independently. Gene silencing effects were progressively enhanced as the number of the siRNA in each pRNA-X nanoparticles gradually increased from one to two, three, and four. More importantly, systemic injection of ligand-containing nanoparticles into the tail-vein of mice revealed that the RNA nanoparticles remained intact and strongly bound to cancers without entering the liver, lung or any other organs or tissues, while remaining in cancer tissue for more than 8 h.

Original language	English
Pages (from-to)	245-257
Number of pages	13
Journal	Nano Today
Volume	7
Issue number	4
DOIs	https://doi.org/10.1016/j.nantod.2012.06.010
State	Published - Aug 2012

Bibliographical note

Funding Information:
The research was supported by NIH Grants EB003730 and CA151648 to P.G. AFM images were obtained at Nanoimaging Core Facility supported by NIH SIG program, and UNMC Program of ENRI. We thank Dr. Zhenqi Zhu from Dr. Malak Kotb's Lab at University of Cincinnati for help with the T M assays. PG is a cofounder of Kylin Therapeutics, Inc., and Biomotor and Nucleic Acid Nanotechnology Development Corp. Ltd.

Funding Information:
Dr. Peixuan Guo , Ph.D., is William Farish Endowed Chair in Nanobiotechnology, Markey Cancer Center, professor of College of Pharmacy at University of Kentucky, and director of NIH/NCI Cancer Nanotechnology Platform Partnership Program: “RNA Nanotechnology for Cancer Therapy”. He obtained his Ph.D. from University of Minnesota, and postdoctoral training at NIH, joined Purdue University in 1990, was tenured in 1993, became a full Professor in 1997, and was honored as a Purdue Faculty Scholar in 1998. He constructed phi29 DNA-packaging motor, discovered phi29 motor pRNA, pioneered RNA nanotechnology, incorporated phi29 motor channel into lipid membranes for single-molecule sensing with potential for high-throughput dsDNA sequencing. He is a member of two prominent national nanotech initiatives sponsored by NIH, NSF, NIST, and National Council of Nanotechnology, director of one NIH Nanomedicine Development Center from 2006 to 2011. His work was featured hundreds of times over radio or TV such as ABC, NBC, newsletters NIH, NSF, MSNBC, NCI, ScienceNow, etc. http://www.eng.uc.edu/nanomedicine/peixuanguo.html

Keywords

Bacteriophage phi29
DNA packaging motor
Nanobiotechnology
Nanomotor
Nanotechnology
RNA nanoparticle
RNA nanotechnology
RNA therapeutics

ASJC Scopus subject areas

Biotechnology
Bioengineering
Biomedical Engineering
Materials Science (all)
Pharmaceutical Science

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.nantod.2012.06.010

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title = "Ultrastable synergistic tetravalent RNA nanoparticles for targeting to cancers",

abstract = "One of the advantages of nanotechnology is the feasibility to construct therapeutic particles carrying multiple therapeutics with defined structure and stoichiometry. The field of RNA nanotechnology is emerging. However, controlled assembly of stable RNA nanoparticles with multiple functionalities which retain their original role is challenging due to refolding after fusion. Herein, we report the construction of thermodynamically stable X-shaped RNA nanoparticles to carry four therapeutic RNA motifs by self-assembly of reengineered small RNA fragments. We proved that each arm of the four helices in the X-motif can harbor one siRNA, ribozyme, or aptamer without affecting the folding of the central pRNA-X core, and each daughter RNA molecule within the nanoparticle folds into their respective authentic structures and retains their biological and structural function independently. Gene silencing effects were progressively enhanced as the number of the siRNA in each pRNA-X nanoparticles gradually increased from one to two, three, and four. More importantly, systemic injection of ligand-containing nanoparticles into the tail-vein of mice revealed that the RNA nanoparticles remained intact and strongly bound to cancers without entering the liver, lung or any other organs or tissues, while remaining in cancer tissue for more than 8 h.",

keywords = "Bacteriophage phi29, DNA packaging motor, Nanobiotechnology, Nanomotor, Nanotechnology, RNA nanoparticle, RNA nanotechnology, RNA therapeutics",

author = "Farzin Haque and Dan Shu and Yi Shu and Shlyakhtenko, {Luda S.} and Rychahou, {Piotr G.} and {Mark Evers}, B. and Peixuan Guo",

note = "Funding Information: The research was supported by NIH Grants EB003730 and CA151648 to P.G. AFM images were obtained at Nanoimaging Core Facility supported by NIH SIG program, and UNMC Program of ENRI. We thank Dr. Zhenqi Zhu from Dr. Malak Kotb's Lab at University of Cincinnati for help with the T M assays. PG is a cofounder of Kylin Therapeutics, Inc., and Biomotor and Nucleic Acid Nanotechnology Development Corp. Ltd. Funding Information: Dr. Peixuan Guo , Ph.D., is William Farish Endowed Chair in Nanobiotechnology, Markey Cancer Center, professor of College of Pharmacy at University of Kentucky, and director of NIH/NCI Cancer Nanotechnology Platform Partnership Program: “RNA Nanotechnology for Cancer Therapy”. He obtained his Ph.D. from University of Minnesota, and postdoctoral training at NIH, joined Purdue University in 1990, was tenured in 1993, became a full Professor in 1997, and was honored as a Purdue Faculty Scholar in 1998. He constructed phi29 DNA-packaging motor, discovered phi29 motor pRNA, pioneered RNA nanotechnology, incorporated phi29 motor channel into lipid membranes for single-molecule sensing with potential for high-throughput dsDNA sequencing. He is a member of two prominent national nanotech initiatives sponsored by NIH, NSF, NIST, and National Council of Nanotechnology, director of one NIH Nanomedicine Development Center from 2006 to 2011. His work was featured hundreds of times over radio or TV such as ABC, NBC, newsletters NIH, NSF, MSNBC, NCI, ScienceNow, etc. http://www.eng.uc.edu/nanomedicine/peixuanguo.html",

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AU - Mark Evers, B.

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Ultrastable synergistic tetravalent RNA nanoparticles for targeting to cancers

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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