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

DNAzyme has emerged as a promising gene silencer for therapeutic applications. However, DNAzymebased gene therapy against tumors is still challenged by undesired cytotoxicity in normal cells. Herein, we explored the potential application of hybridization chain reaction (HCR) for endogenous miRNA-activated DNAzyme-based gene silencing, which performing amplified signal and cellular onsite therapy in one system. The DNA probes, called HCR-tDz circuits, are designed by combining HCR and therapeutic DNAzyme (tDz). The miRNA-21 is selected as the diagnostic target for its distinctive overexpression in cancerous cells, and the HCR is employed to amplify the miR-21 recognition event as well as the tDz activation. The massively repeated DNAzyme activated by miR-21-triggered HCR is utilized to catalytically cleave early growth response-1 mRNA and implement a cellular gene-silencing strategy. Results show that HCR-tDz nanostructure enables amplified miR-21 imaging in living cells. Furthermore, this nanosystem can effectively inhibit the proliferation of cancer cells with high specificity, thus resulting in sensitive diagnostic signaling and accurate therapeutic effects.