Logic-gated tumor-microenvironment nanoamplifier enables targeted delivery of CRISPR/Cas9 for multimodal cancer therapy

• Published in: Acta pharmaceutica Sinica. B 2024-02, Vol.14 (2), p.795-807
• Main Authors: Pan, Yongchun, Luan, Xiaowei, Zeng, Fei, Wang, Xuyuan, Qin, Shurong, Lu, Qianglan, He, Guanzhong, Gao, Yanfeng, Sun, Xiaolian, Han, Xin, He, Bangshun, Song, Yujun
• Format: Article
• Language: English
• Subjects: CRISPR delivery; Enzyme encapsulation; Gene editing; Hybrid material; Hypoxia; Logic gate; Multimodal therapy; Original; Precise nanomedicine
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2023.09.016

Recent innovations in nanomaterials inspire abundant novel tumor-targeting CRISPR-based gene therapies. However, the therapeutic efficiency of traditional targeted nanotherapeutic strategies is limited by that the biomarkers vary in a spatiotemporal-dependent manner with tumor progression. Here, we propose a self-amplifying logic-gated gene editing strategy for gene/H2O2-mediated/starvation multimodal cancer therapy. In this approach, a hypoxia-degradable covalent-organic framework (COF) is synthesized to coat a-ZIF-8 in which glucose oxidase (GOx) and CRISPR system are packaged. To intensify intracellular redox dyshomeostasis, DNAzymes which can cleave catalase mRNA are loaded as well. When the nanosystem gets into the tumor, the weakly acidic and hypoxic microenvironment degrades the ZIF-8@COF to activate GOx, which amplifies intracellular H+ and hypoxia, accelerating the nanocarrier degradation to guarantee available CRISPR plasmid and GOx release in target cells. These tandem reactions deplete glucose and oxygen, leading to logic-gated-triggered gene editing as well as synergistic gene/H2O2-mediated/starvation therapy. Overall, this approach highlights the biocomputing-based CRISPR delivery and underscores the great potential of precise cancer therapy. Hypoxia “AND” acid responsive CRISPR delivery system with self-amplifying degradation were constructed for early cancer treatment where less biomarker existed in the tumor microenvironment. [Display omitted]