Self‐Adaptive Activation of DNAzyme Nanoassembly for Synergistically Combined Gene Therapy

Abstract DNAzyme represents a promising gene silencing toolbox yet is obstructed by the poor substrate accessibility in specific cells. Herein, a compact DNA nanoassembly, incorporating multimeric therapeutic DNAzyme, was prepared for selective delivery of gene‐silencing DNAzyme with requisite cofactors and auxiliary chemo‐drugs. By virtue of the sequence‐conservative duplex‐specific nuclease, the endogenous miRNA catalyzes the successive and site‐specific cleavage of DNA nanoassembly substrate (nominated as the localized RNA walking machine) and thus ensures the liberation/activation of therapeutic agents with high accuracy and efficacy. The miR‐10b‐stimulated DNAzyme was designed to downregulate the TWIST transcription factor, an upstream promotor of miR‐10b, thus acquiring the self‐sufficient downregulation of TWIST/miR‐10b signaling nodes (self‐adaptive negative feedback loop) for abrogating tumor metastasis and chemo‐resistance issues.