Logic-gated tumor-microenvironment nanoamplifier enables targeted delivery of CRISPR/Cas9 for multimodal cancer therapy.
10.1016/j.apsb.2023.09.016
- Author:
Yongchun PAN
1
;
Xiaowei LUAN
2
;
Fei ZENG
2
;
Xuyuan WANG
2
;
Shurong QIN
2
;
Qianglan LU
2
;
Guanzhong HE
2
;
Yanfeng GAO
2
;
Xiaolian SUN
3
;
Xin HAN
4
;
Bangshun HE
1
;
Yujun SONG
2
Author Information
1. Department of Laboratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China.
2. College of Engineering and Applied Sciences, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing 210023, China.
3. State Key Laboratory of Natural Medicines, Key Laboratory of Drug Quality Control and Pharmacovigilance, Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 211198, China.
4. School of Medicine & Holistic Integrative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing 210023, China.
- Publication Type:Journal Article
- Keywords:
CRISPR delivery;
Enzyme encapsulation;
Gene editing;
Hybrid material;
Hypoxia;
Logic gate;
Multimodal therapy;
Precise nanomedicine
- From:
Acta Pharmaceutica Sinica B
2024;14(2):795-807
- CountryChina
- Language:English
-
Abstract:
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.
