深圳大学董海峰团队报道了生物标志物驱动治疗的AND逻辑门激活CRISPR/RNA适体系统。相关研究成果于2024年12月19日发表在《美国化学会杂志》。

迫切需要开发一种能够检测多种生物标志物的工程RNA装置，以评估病理状态并自主实施反应性治疗。

该文中，研究人员报告了一种集成的纳米CRISPR Cas13a/RNA适配体治疗平台，InCasApt，其能够实现生物标志物检测和生物标志物驱动的治疗。在该系统中，Cas13a/crRNA复合物、发夹报告子（HR）、二硝基苯胺笼状Ce6光敏剂（Ce6-DN）和DN结合RNA适配体前体（DNBApt）以受控方式被装载到树枝状介孔硅纳米颗粒（DMSN）上。

虽然InCasApt在正常细胞中保持惰性，但其可编程的治疗诊断能力在致癌miRNA-155和miRNA-21表达升高的肿瘤细胞中被激活。这些miRNA充当AND逻辑门，产生用于疾病状况评估的荧光和用于光动力治疗的ROS。

该过程还上调抑癌基因BRG1，并通过抑制miRNA-155和miRNA-21的功能来抑制肿瘤迁移。这些效应突显了InCasApt作为，弥合诊断和治疗之间差距的miRNA靶向策略的多功能性。

附：英文原文

Title: CRISPR/RNA Aptamer System Activated by an AND Logic Gate for Biomarker-Driven Theranostics

Author: Qiqi Yang, Ming-Jie Dong, Jianglian Xu, Yi Xing, Yue Wang, Jinlong Yang, Xiangdan Meng, Tianzhen Xie, Yingfu Li, Haifeng Dong

Issue&Volume: December 19, 2024

Abstract: The development of an engineered RNA device capable of detecting multiple biomarkers to evaluate pathological states and autonomously implement responsive therapies is urgently needed. Here, we report InCasApt, an integrated nano CRISPR Cas13a/RNA aptamer theranostic platform capable of achieving both biomarker detection and biomarker-driven therapy. Within this system, a Cas13a/crRNA complex, a hairpin reporter (HR), a dinitroaniline caged Ce6 photosensitizer (Ce6-DN), and a DN-binding RNA aptamer precursor (DNBApt) are coloaded onto dendritic mesoporous silicon nanoparticles (DMSN) in a controlled manner. While InCasApt remains inert in normal cells, its programmable theranostic capabilities are activated in tumor cells that have elevated expression of carcinogenic miRNA-155 and miRNA-21. These miRNAs act as an AND logic gate, generating fluorescence for disease condition evaluation and ROS for photodynamic therapy. This process also upregulates antioncogene BRG1 and suppresses tumor migration by inhibiting the function of miRNA-155 and miRNA-21. These effects underscore the versatility of InCasApt as an miRNA-targeting strategy for bridging the gap between diagnosis and therapy.

DOI: 10.1021/jacs.4c08719

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.4c08719