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

作者：Jing Wang, Jinhua Shang, Shanshan Yu, Mengru Lin, Xue Gong, Xiaoqing Liu, Zhihong Liu, Fuan Wang · 发表于：Angewandte Chemie International Edition · 年份：2024 · DOI：10.1002/anie.202417363 · 被引用次数：19 · 研究领域：Advanced biosensing and bioanalysis techniques、RNA Interference and Gene Delivery、CRISPR and Genetic Engineering

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.