Rational design for controlled release of Dicer-substrate siRNA harbored in phi29 pRNA-based nanoparticles

Daniel W. Binzel, Songchuan Guo, Hongran Yin, Tae Jin Lee, Shujun Liu, Dan Shu, Peixuan Guo

Research output: Contribution to journalArticlepeer-review

Abstract

Small interfering RNA (siRNA) for silencing genes and treating disease has been a dream since ranking as a top Breakthrough of the Year in 2002 by Science. With the recent FDA approval of four siRNA-based drugs, the potential of RNA therapeutics to become the third milestone in pharmaceutical drug development has become a reality. However, the field of RNA interference (RNAi) therapeutics still faces challenges such as specificity in targeting, intracellular processing, and endosome trapping after targeted delivery. Dicer-substrate siRNAs included onto RNA nanoparticles may be able to overcome these challenges. Here, we show that pRNA-based nanoparticles can be designed to efficiently harbor the Dicer-substrate siRNAs in vitro and in vivo to the cytosol of tumor cells and release the siRNA. The structure optimization and chemical modification for controlled release of Dicer-substrate siRNAs in tumor cells were also evaluated through molecular beacon analysis. Studies on the length requirement of the overhanging siRNA revealed that at least 23 nucleotides at the dweller's arm were needed for dicer processing. The above sequence parameters and structure optimization were confirmed in recent studies demonstrating the release of functional Survivin siRNA from the pRNA-based nanoparticles for cancer inhibition in non-small-cell lung, breast, and prostate cancer animal models.

Original languageEnglish (US)
Pages (from-to)524-535
Number of pages12
JournalMolecular Therapy - Nucleic Acids
Volume25
DOIs
StatePublished - Sep 3 2021

Bibliographical note

Funding Information:
The work was mainly supported by NIH Grants U01CA207946 and R01EB019036 to P.G. and partially supported by NIH Grant R01CA257961 to D.S. and D.W.B. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. P.G.’s Sylvan G. Frank Endowed Chair position in Pharmaceutics and Drug Delivery is funded by the CM Chen Foundation . Confocal images presented in this report were generated with the instruments and services at the Campus Microscopy and Imaging Facility, The Ohio State University. This facility is supported in part by Grant P30 CA016058 , National Cancer Institute , Bethesda, MD.

Funding Information:
The work was mainly supported by NIH Grants U01CA207946 and R01EB019036 to P.G. and partially supported by NIH Grant R01CA257961 to D.S. and D.W.B. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. P.G.?s Sylvan G. Frank Endowed Chair position in Pharmaceutics and Drug Delivery is funded by the CM Chen Foundation. Confocal images presented in this report were generated with the instruments and services at the Campus Microscopy and Imaging Facility, The Ohio State University. This facility is supported in part by Grant P30 CA016058, National Cancer Institute, Bethesda, MD. Conceptualization, P.G. D.S. and S.G.; methodology, S.G. H.Y. P.G. and T.J.L.; investigation, S.G. H.Y. and T.J.L.; writing?original draft, H.Y. D.W.B. and P.G.; writing?review & editing, D.W.B. S.L. D.S. and P.G.; visualization, D.W.B. S.G. and P.G.; funding acquisition, P.G. P.G. is the consultant of Oxford Nanopore Technologies, the cofounder of Shenzhen P&Z Bio-medical Co. Ltd, as well as cofounder of ExonanoRNA, LLC.

Publisher Copyright:
© 2021 The Author(s)

Keywords

  • RNA for cancer therapy
  • RNA nanotechnology
  • RNA therapeutics
  • dicer processing
  • exosomes
  • gene regulation
  • nanobiotechnology
  • siRNA delivery

PubMed: MeSH publication types

  • Journal Article

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