Targeted and direct intracellular delivery of native DNAzymes enables highly specific gene silencing

Abstract

DNAzymes exhibit high potentials 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...

In Situ Modulating DNAzyme Activity and Internalization Behavior with Acid-Initiated Reconfigurable DNA Nanodevice for Activatable Theranostic

“…Currently, increasing studies have focused on DNAzyme mediated cancer theranostics, via cleaving tumorigenic RNA (e.g., mRNA, microRNA). − Although significant progress both in vitro and in vivo has achieved, the clinical validation of DNAzymes is still challenged by off-target toxicity for lack of specificity . To overcome this challenge, a variety of active targeting strategies have developed by equipping the DNAzyme-delivery systems with affinity ligands (e.g., folate, aptamer), which can selectively bind receptors overexpressed on target tumor cells, thus facilitating specific homing and endocytosis. , However, in most cases, the ligand targeted antigens are also expressed in healthy cells at a low level, which inevitably entail unintended cellular uptake, therefore compromising the therapeutic benefits. , Especially, large as well as multivalent delivery systems tend to aggravate the undesired endocytosis, despite improved interaction with target tumor cells.…”

Stimuli Responsive, Programmable DNA Nanodevices for Biomedical Applications

“…These DNAzymes identify and cleave the marked Egr-1 gene to achieve the gene-silencing function ( Figure 5B ). The Apt/Dz nanostructure shows the advantages of targeted delivery, better stability, nontoxicity, and reduces side effects which are essential in using DNAzymes as therapeutic drug ( Li et al, 2020 ).…”

“… (A) Construction of the Apt/Dz constrained catenane nanostructure and (B) the representation of targeted delivery of the Apt/Dz nanostructure for gene silencing into cancer cells. Reproduced with permission from ref Li et al (2020) . Copyright 2020, The Royal Society of Chemistry (RSC).…”

An Endogenous miRNA-Initiated Hybridization Chain Reaction and Subsequent DNAzyme Activation for Cellular Theranostics

“…[1][2] It has been sustainedly considered as powerful therapeutic approaches for multitudinous cancers due to its low toxicity and high efficiency. [3][4] Among these therapeutics strategies, antisense oligonucleotides, short-interference RNAs (siRNA), ribozymes, DNAzymes are several common agents under development. 5 In particular, DNAzymes have been identified as prominent therapeutic tactic that successively catalyze the hydrolysis of oncogene mRNAs without kidnapping their cellular machinery.…”

“…[10][11][12][13] Despite these advantages, DNAzyme-based gene therapy in tumors is still in its infancy stage of scientific research and restrained by controllable and exclusive activation in cancer cells while avoiding undesired cytotoxicity in normal cells. 3,14 Light irradiation is one representatively activatable strategy to restore DNAzyme activity, which modifies photocaging groups on DNAzymes to regulate the hybridization ability with their target mRNA. [15][16] Although exhibiting high degree of spatial and temporal control, these therapeutic designs that depend on external intervention are still unable to implement gene regulation autonomously according to endogenous cellular information.…”