3D RNA nanocage for encapsulation and shielding of hydrophobic biomolecules to improve the in vivo biodistribution
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3D RNA nanocage for encapsulation and shielding of hydrophobic biomolecules to improve the in vivo biodistribution Congcong Xu1, Kaiming Zhang2, Hongran Yin1, Zhefeng Li1, Alexey Krasnoslobodtsev3,4, Zhen Zheng1, Zhouxiang Ji1, Sijin Guo1, Shanshan Li2, Wah Chiu2,5, and Peixuan Guo1 () 1
Center for RNA Nanobiotechnology and Nanomedicine, College of Pharmacy, Division of Pharmaceutics and Pharmaceutical Chemistry, College of Medicine, Dorothy M. Davis Heart and Lung Research Institute, James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA 2 Department of Bioengineering, James H. Clark Center, Stanford University, Stanford, CA 94305, USA 3 Department of Physics, University of Nebraska at Omaha, Omaha, NE 68182, USA 4 Nanoimaging Core Facility, Office of Vice-Chancellor for Research, University of Nebraska Medical Center, Omaha, NE 68198, USA 5 SLAC National Accelerator Laboratory, Stanford University, Menlo Park, CA 94025, USA © Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2020 Received: 9 June 2020 / Revised: 16 July 2020 / Accepted: 18 July 2020
ABSTRACT Ribonucleic acid (RNA) nanotechnology platforms have the potential of harboring therapeutics for in vivo delivery in disease treatment. However, the nonspecific interaction between the harbored hydrophobic drugs and cells or other components before reaching the diseased site has been an obstacle in drug delivery. Here we report an encapsulation strategy to prevent such nonspecific hydrophobic interactions in vitro and in vivo based on a self-assembled three-dimensional (3D) RNA nanocage. By placing an RNA three-way junction (3WJ) in the cavity of the nanocage, the conjugated hydrophobic molecules were specifically positioned within the nanocage, preventing their exposure to the biological environment. The assembly of the nanocages was characterized by native polyacrylamide gel electrophoresis (PAGE), atomic force microscopy (AFM), and cryogenic electron microscopy (cryo-EM) imaging. The stealth effect of the nanocage for hydrophobic molecules in vitro was evaluated by gel electrophoresis, flow cytometry, and confocal microscopy. The in vivo sheathing effect of the nanocage for hydrophobic molecules was assessed by biodistribution profiling in mice. The RNA nanocages with hydrophobic biomolecules underwent faster clearance in liver and spleen in comparison to their counterparts. Therefore, this encapsulation strategy holds promise for in vivo delivery of hydrophobic drugs for disease treatment.
KEYWORDS ribonucleic acid (RNA) nanocage, three-way junction (3WJ), encapsulation, hydrophobic biomolecule, RNA nanotechnology
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Introduction
The past decades witnessed the rapid development of nanotechnology-enabled therapeutics and medical devices [1]. However, the biggest hurdle to the clinical translation of nanotechnology lies in the biological barriers wherein the nonspecific cellular interaction and undesirable organ accumulation occur [2, 3]. Accumulation of nanoparticles in healthy organs,
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