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

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外文摘要：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 multi-modal cancer therapy.In this approach,a hypoxia-degradable covalent-organic framework(COF)is syn-thesized 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 nano-carrier 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.

外文关键词：

CRISPR deliveryEnzyme encapsulationLogic gateHybrid materialHypoxiaGene editingPrecise nanomedicineMultimodal therapy

作者：

Yongchun Pan、Xiaowei Luan、Fei Zeng、Xuyuan Wang、Shurong Qin、Qianglan Lu、Guanzhong He、Yanfeng Gao、Xiaolian Sun、Xin Han、Bangshun He、Yujun Song

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作者单位：

Department of Laboratory Medicine,Nanjing First Hospital,Nanjing Medical University,Nanjing 210006,China

College of Engineering and Applied Sciences,State Key Laboratory of Analytical Chemistry for Life Science,Nanjing University,Nanjing 210023,China

State Key Laboratory of Natural Medicines,Key Laboratory of Drug Quality Control and Pharmacovigilance,Department of Pharmaceutical Analysis,China Pharmaceutical University,Nanjing 211198,China

School of Medicine & Holistic Integrative Medicine,Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization,Nanjing University of Chinese Medicine,Nanjing 210023,China

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基金：

National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Key R&D Program of ChinaKey Research and Development Program of Jiangsu Province,ChinaJiangsu Provincial Medical Key Discipline Cultivation Unit,ChinaNatural Science Foundation of Jiangsu Province,ChinaFundamental Research Funds for Central Universities(China)Program for Innovative Talents and Entrepreneur in Jiangsu(China)Postgraduate Research & Practice Innovation Program of Jiangsu Province,China

项目编号：

21874066820732882019YFA0709200BE2021373JSDW202239BK20200336KYCX23_0146

出版年：

2024

DOI：

10.1016/j.apsb.2023.09.016

药学学报(英文版)

CSTPCD

ISSN：

年,卷(期)：2024.14(2)

参考文献量36