Luo Dan, Lin Xue, Zhao Yun, Hu Jialing, Mo Fengye, Song Gege, Zou Zhiqiao, Wang Fuan, Liu Xiaoqing
College of Chemistry and Molecular Sciences, Wuhan University 430072 Wuhan P. R. China
Chem Sci. 2022 Mar 28;13(18):5155-5163. doi: 10.1039/d2sc00459c. eCollection 2022 May 11.
Nucleic acid therapeutics has reached clinical utility through modulating gene expression. As a potential oligonucleotide drug, DNAzyme has RNA-cleaving activity for gene silencing, but faces challenges due to the lack of a safe and effective delivery vehicle and low catalytic activity. Here we describe DNAzyme-mediated gene regulation using dynamic DNA nanomaterials with intrinsic biocompatibility, stability, tumor-targeted delivery and uptake, and self-enhanced efficacy. We assemble programmable DNA nanosponges to package and deliver diverse nucleic acid drugs and therapeutic agents such as aptamer, DNAzyme and its cofactor precursor, and photosensitizer in one pot through the rolling circle amplification reaction, formulating a controllable nanomedicine using encoded instructions. Upon environmental stimuli, DNAzyme activity increases and RNA cleavage accelerates by a supplementary catalytic cofactor. In addition, this approach induces elevated O and O generation as auxiliary treatment, achieving simultaneously self-enhanced gene-photodynamic cancer therapy. These findings may advance the clinical trial of oligonucleotide drugs as tools for gene modulation.
核酸疗法已通过调节基因表达实现了临床应用。作为一种潜在的寡核苷酸药物，脱氧核酶具有用于基因沉默的RNA切割活性，但由于缺乏安全有效的递送载体以及催化活性低而面临挑战。在此，我们描述了使用具有内在生物相容性、稳定性、肿瘤靶向递送和摄取以及自我增强疗效的动态DNA纳米材料进行脱氧核酶介导的基因调控。我们组装可编程的DNA纳米海绵，通过滚环扩增反应在一个反应体系中包装并递送多种核酸药物和治疗剂，如适体、脱氧核酶及其辅因子前体以及光敏剂，利用编码指令构建可控的纳米药物。在环境刺激下，脱氧核酶活性增加，并且通过补充催化辅因子加速RNA切割。此外，这种方法诱导产生更多的单线态氧和三线态氧作为辅助治疗手段，实现了同时自我增强的基因-光动力癌症治疗。这些发现可能会推动寡核苷酸药物作为基因调节工具的临床试验。
