【IF29.4】超声可控和ros敏感CRISPR-Cas9基因组编辑用于增强/协同超声肿瘤纳米治疗
杂志名称:Advanced Materials
影响因子:29.4
文章题目:Sono-Controllable and ROS-Sensitive CRISPR-Cas9 Genome Editing for Augmented/Synergistic Ultrasound Tumor Nanotherapy
文献地址:https://doi.org/10.1002/adma.202104641
第一作者:
Yinying Pu、Haohao Yin、Caihong Dong、Huijing Xiang、Wencheng Wu、Bangguo Zhou、 Dou Du、Yu Chen、Huixiong Xu
作者单位:
上海市第十人民医院医学超声科肿瘤微创治疗中心;
同济大学医学院超声研究与教育研究所介入医学临床研究中心;
上海市超声诊断工程技术研究中心和治疗国家介入医学临床研究中心;
上海市器官修复工程技术研究中心Materdicine实验室;
上海大学生命科学学院;
复旦大学,上海医学影像研究所,中山医院超声科;
中国科学院上海陶瓷研究所微观结构高性能陶瓷与超微陶瓷国家重点实验室
引用产品:
fetal bovine serum(FBS)
文章摘要: The potential of the cluster regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (Cas9)-based therapeutic genome editing is severely hampered by the difficulties in precise regulation of the in vivo activity of the CRISPR-Cas9 system. Herein, sono-controllable and reactive oxygen species (ROS)-sensitive sonosensitizer-integrated metal–organic frameworks (MOFs), denoted as P/M@CasMTH1, are developed for augmented sonodynamic therapy (SDT) efficacy using the genome-editing technology. P/M@CasMTH1 nanoparticles comprise singlet oxygen (1O2)-generating MOF structures anchored with CRISPR-Cas9 systems via 1O2-cleavable linkers, which serve not only as a delivery vector of CRISPR-Cas9 targeting MTH1, but also as a sonoregulator to spatiotemporally activate the genome editing. P/M@CasMTH1 escapes from the lysosomes, harvests the ultrasound (US) energy and converts it into abundant 1O2 to induce SDT. The generated ROS subsequently trigger cleavage of ROS-responsive thioether bonds, thus inducing controllable release of the CRISPR-Cas9 system and initiation of genome editing. The genomic disruption of MTH1 conspicuously augments the therapeutic efficacy of SDT by destroying the self-defense system in tumor cells, thereby causing cellular apoptosis and tumor suppression. This therapeutic strategy for synergistic MTH1 disruption and abundant 1O2 generation provides a paradigm for augmenting SDT efficacy based on the emerging nanomedicine-enabled genome-editing technology.
基于簇规则间隔短回文重复(CRISPR)相关蛋白9 (Cas9)的治疗性基因组编辑的潜力受到CRISPR-Cas9系统体内活性精确调控的困难的严重阻碍。本文利用基因组编辑技术,开发了超声可控和活性氧(ROS)敏感的声敏剂集成金属有机框架(mof),表示为P/M@CasMTH1,用于增强声动力治疗(SDT)疗效。P/M@CasMTH1纳米颗粒包含产生单线态氧(1O2)的MOF结构,通过可切割的10o2连接物与CRISPR-Cas9系统锚定,不仅作为靶向MTH1的CRISPR-Cas9的传递载体,而且作为时空激活基因组编辑的声调节因子。P/M@CasMTH1从溶酶体中逃逸,获取超声(US)能量,并将其转化为丰富的1O2诱导SDT。产生的ROS随后触发ROS响应的硫醚键的切割,从而诱导CRISPR-Cas9系统的可控释放和基因组编辑的启动。MTH1的基因组破坏通过破坏肿瘤细胞的自我防御系统,从而导致细胞凋亡和肿瘤抑制,显著增强了SDT的治疗效果。这种协同MTH1破坏和丰富的1O2生成的治疗策略为基于新兴的纳米医学基因组编辑技术增强SDT疗效提供了一个范例。