4.7 Article

An intelligent DNA nanomachine for amplified MicroRNA imaging and MicroRNA-Guided efficient gene silencing

Journal

TALANTA
Volume 265, Issue -, Pages -

Publisher

ELSEVIER
DOI: 10.1016/j.talanta.2023.124820

Keywords

DNA Nanomachine; MicroRNA; DNAzyme; Cascade reaction; Gene silencing

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We developed a miRNA-responsive DNAzyme cascaded catalytic (MDCC) nanomachine for amplified intracellular miRNA imaging and miRNA-guided efficient gene silencing. The intelligent MDCC nanomachine consists of multiple DNAzyme subunit-encoded catalyzed hairpin assembly (CHA) reactants sustained by pH-responsive Zeolitic imidazolate framework-8 (ZIF-8) nanoparticles. Through a catalytic hairpin assembly (CHA) reaction triggered by the presence of miRNA-21, a large number of Y-shaped fluorescent DNA constructs containing three DNAzyme modules are generated for gene silencing. This strategy provides a promising platform for highly sensitive determination of biomolecules and accurate gene therapy of cancer cells.
The DNA nanomachines as excellent synthetic biological tools have been widely used for the sensitive detection of intracellular microRNA (miRNA) and DNAzyme-involved gene silencing. However, intelligent DNA nanomachines which have the ability to sense intracellular specific biomolecules and respond to external information in complex environments still remain challenging. Herein, we develop a miRNA-responsive DNAzyme cascaded catalytic (MDCC) nanomachine to perform multilayer cascade reactions, enabling the amplified intracellular miRNA imaging and miRNA-guided efficient gene silencing. The intelligent MDCC nanomachine is designed based on multiple DNAzyme subunit-encoded catalyzed hairpin assembly (CHA) reactants sustained by the pHresponsive Zeolitic imidazolate framework-8 (ZIF-8) nanoparticles. After cellular uptake, the MDCC nanomachine degrades in acidic endosome and releases three hairpin DNA reactants and Zn2+, and the latter can act as an effective cofactor for DNAzyme. In the presence of miRNA-21, a catalytic hairpin assembly (CHA) reaction is triggered, which produces a large number of Y-shaped fluorescent DNA constructs containing three DNAzyme modules for gene silencing. The construction of Y-shaped DNA modified with multisite fluorescence and the circular reaction realizes ultrasensitive miRNA-21 imaging of cancer cells. Moreover, miRNA-guided gene silencing inhibits the cancer cell proliferation through the DNAzyme-specific recognition and cleavage of target EGR-1 (Early Growth Response-1) mRNA, which is one key tumor-involved mRNA. The strategy may provide a promising platform for highly sensitive determination of biomolecules and accurate gene therapy of cancer cells.

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