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Conditional Deoxyribozyme-Nanoparticle Conjugates for miRNA-Triggered Gene Regulation.

Jiahui Zhang1, Rong Ma2, Aaron Blanchard1

  • 1Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia 30332, United States.

ACS Applied Materials & Interfaces
|August 18, 2020
PubMed
Summary

Researchers developed conditional DNA-nanoparticles (conditional DzNPs) that activate gene silencing only when specific RNA triggers are present. This advance offers greater control for targeted gene regulation therapy, potentially leading to more specific nucleic acid therapeutics.

Keywords:
DNA−NP conjugatesTNFαconditional gene regulationdeoxyribozymemacrophagesmiR-33

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Area of Science:

  • Biotechnology
  • Molecular Biology
  • Gene Therapy

Background:

  • DNA-nanoparticle (NP) conjugates are effective for transient gene knockdown but lack cell-type specificity.
  • Constitutive activity and rapid uptake limit precise control in gene regulation therapy.

Purpose of the Study:

  • To develop controllable DNA-NPs with enhanced tissue or cell type specificity.
  • To create responsive nucleic acid therapeutics using molecular programming for targeted gene regulation.

Main Methods:

  • Incorporation of toehold-mediated strand exchange to create conditional DNA-nanoparticles (conditional DzNPs).
  • Design of conditional DzNPs to target tumor necrosis factor α (TNFα) mRNA, triggered by miR-33.
  • Optimization of conditional DzNP preparation, configuration, and toehold length for specific RNA response.

Main Results:

  • Demonstrated specific and strong ON/OFF switching of conditional DzNPs in response to miR-33 trigger in buffer.
  • Showcased toehold-mediated strand exchange and restoration of TNFα DNAzyme activity upon miR-33 presence.
  • Successfully achieved endogenous miR-33-triggered knockdown of TNFα mRNA in mouse macrophages.

Conclusions:

  • Conditional DzNPs offer a novel approach for responsive gene regulation with enhanced specificity.
  • This technology holds potential for developing targeted nucleic acid therapeutics and conditional gene regulation applications.