东南大学周志新团队报道了基于核酸的结构动态网络在细胞内成像和时空可编程基因治疗中的空间定域熵驱动演化。相关研究成果发表在2024年7月16日出版的《美国化学会杂志》。

介绍了基于DNA的组成动态网络CDN的引物引导熵驱动高通量进化。与该过程相关的熵增益为CDN的放大出现提供了催化原理。该概念被应用于开发可编程、空间定位的DNA电路，用于癌症细胞的体外和体内有效治疗、基因调节治疗。

局部电路由一个DNA四面体核心组成，四面体核心在其四角处被修饰，其中包括编码的碱基序列，这些序列具有出现和组装成[2×2]CDN的能力。

其中两根链被一对siRNA亚基束缚，将电路阻断为一个沉默、动态失活的配置。在miRNA-21作为引物的情况下，siRNA亚基被置换，导致siRNA的扩增释放，沉默HIF-1αmRNA，并使系链快速动态重组为CDN。

然而，所产生的CDN被miRNA-155动态重新配置为富含DNA酶组分的平衡混合物，催化EGR-1mRNA的切割。DNA四面体纳米结构刺激增强对癌症细胞的渗透。

miRNA-三重的熵驱动的空间定位电路的重新配置导致HIF-1α和EGR-1 mRNA的可编程、协同双基因沉默，导致乳腺癌症细胞的有效和选择性凋亡，并有效抑制荷瘤小鼠的肿瘤。

附：英文原文

Title: Spatially Localized Entropy-Driven Evolution of Nucleic Acid-Based Constitutional Dynamic Networks for Intracellular Imaging and Spatiotemporal Programmable Gene Therapy

Author: Nina Lin, Yu Ouyang, Yunlong Qin, Ola Karmi, Yang Sung Sohn, Songqin Liu, Rachel Nechushtai, Yuanjian Zhang, Itamar Willner, Zhixin Zhou

Issue&Volume: July 16, 2024

Abstract: The primer-guided entropy-driven high-throughput evolution of the DNA-based constitutional dynamic network, CDN, is introduced. The entropy gain associated with the process provides a catalytic principle for the amplified emergence of the CDN. The concept is applied to develop a programmable, spatially localized DNA circuit for effective in vitro and in vivo theranostic, gene-regulated treatment of cancer cells. The localized circuit consists of a DNA tetrahedron core modified at its corners with four tethers that include encoded base sequences exhibiting the capacity to emerge and assemble into a [2 × 2] CDN. Two of the tethers are caged by a pair of siRNA subunits, blocking the circuit into a mute, dynamically inactive configuration. In the presence of miRNA-21 as primer, the siRNA subunits are displaced, resulting in amplified release of the siRNAs silencing the HIF-1α mRNA and fast dynamic reconfiguration of the tethers into a CDN. The resulting CDN is, however, engineered to be dynamically reconfigured by miRNA-155 into an equilibrated mixture enriched with a DNAzyme component, catalyzing the cleavage of EGR-1 mRNA. The DNA tetrahedron nanostructure stimulates enhanced permeation into cancer cells. The miRNA-triggered entropy-driven reconfiguration of the spatially localized circuit leads to the programmable, cooperative bis-gene-silencing of HIF-1α and EGR-1 mRNAs, resulting in the effective and selective apoptosis of breast cancer cells and effective inhibition of tumors in tumor bearing mice.

DOI: 10.1021/jacs.4c03651

Source: https://pubs.acs.org/doi/full/10.1021/jacs.4c03651