Abstract
DNAzymes exhibit high potential as gene silencing agents for therapeutic applications. Such purposes, however, are significantly challenged by the targeted and successful delivery of unmodified DNAzymes into cells with minimal side effects. Here, we set out to formulate and demonstrate a new stimuli-responsive and constrained aptamer/DNAzyme (Apt/Dz) catenane nanostructure for highly specific gene silencing. The rational design of the Apt/Dz catenane nanostructure with the respective integration of the aptamer sequence and the completely closed catenane format enables both the targeted capability and significantly improved nuclease resistance, facilitating the stable and targeted delivery of unmodified Dz into cancer cells. Moreover, the Dz enzymatic activity in the constrained structure can only be conditionally regulated by the specific intracellular mRNA sequences to silence the target gene with highly reduced side effects. Results show that the Apt/Dz catenane nanostructure can effectively inhibit the expression of the target gene and the proliferation of cancer cells with high specificity.
Highlights
Gene silencing involves targeting speci c mRNA sequences in cells to inhibit gene expression before translation.[1,2] Because the inhibition or regulation of the expression of a certain gene via gene silencing can attenuate the invasion, proliferation and migration of cancer cells,[3,4] gene silencing has been increasingly investigated as a novel therapeutic strategy for various cancers and diseases
Of particular interest is that DNAzymes can selectively bind their substrate mRNA sequences, exhibiting catalytic activity comparable to that of protein enzymes to cleave these mRNAs during the translational repression of the target genes
The synthesis of the thymidine kinase 1 (TK1) mRNA-responsive Apt/Dz constrained catenane nanostructure and its application for gene silencing is illustrated in Scheme 1
Summary
Gene silencing involves targeting speci c mRNA sequences in cells to inhibit gene expression before translation.[1,2] Because the inhibition or regulation of the expression of a certain gene via gene silencing can attenuate the invasion, proliferation and migration of cancer cells,[3,4] gene silencing has been increasingly investigated as a novel therapeutic strategy for various cancers and diseases. The Dz enzymatic activity in the constrained structure can only be conditionally regulated by the specific intracellular mRNA sequences to silence the target gene with highly reduced side effects.
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