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

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

doi:10.1021/jacs.4c08719

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

J Am Chem Soc. 2024 Dec 19. doi: 10.1021/jacs.4c08719. Online ahead of print.

Authors

Qiqi Yang^{1

2}, Ming-Jie Dong³, Jianglian Xu¹, Yi Xing², Yue Wang¹, Jinlong Yang¹, Xiangdan Meng², Tianzhen Xie¹, Yingfu Li⁴, Haifeng Dong¹

Affiliations

¹ Marshall Laboratory of Biomedical Engineering, Precision Medicine and Health Research Institute, Shenzhen Key Laboratory for Nano-Biosensing Technology, Guangdong Key Laboratory of Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University, Shenzhen 518060, China.
² Beijing Key Laboratory for Bioengineering and Sensing Technology, Department of Chemistry & Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China.
³ Guangdong Laboratory of Artificial Intelligence and Digital Economy (SZ), Shenzhen 518107, China.
⁴ Michael G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada.

PMID: 39699588
DOI: 10.1021/jacs.4c08719

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.