【IF29.4】超聲可控和ros敏感CRISPR-Cas9基因組編輯用于增強/協同超聲腫瘤納米治療
雜志名稱：Advanced Materials
影響因子：29.4
文章題目：Sono-Controllable and ROS-Sensitive CRISPR-Cas9 Genome Editing for Augmented/Synergistic Ultrasound Tumor Nanotherapy
文獻地址：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
作者單位：
上海市第十人民醫(yī)院醫(yī)學超聲科腫瘤微創(chuàng)治療中心；
同濟大學醫(yī)學院超聲研究與教育研究所介入醫(yī)學臨床研究中心；
上海市超聲診斷工程技術研究中心和治療國家介入醫(yī)學臨床研究中心；
上海市器官修復工程技術研究中心Materdicine實驗室；
上海大學生命科學學院；
復旦大學，上海醫(yī)學影像研究所，中山醫(yī)院超聲科；
中國科學院上海陶瓷研究所微觀結構高性能陶瓷與超微陶瓷國家重點實驗室
引用產品：
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.
基于簇規(guī)則間隔短回文重復(CRISPR)相關蛋白9 (Cas9)的治療性基因組編輯的潛力受到CRISPR-Cas9系統(tǒng)體內活性精確調控的困難的嚴重阻礙。本文利用基因組編輯技術，開發(fā)了超聲可控和活性氧(ROS)敏感的聲敏劑集成金屬有機框架(mof)，表示為P/M@CasMTH1，用于增強聲動力治療(SDT)療效。P/M@CasMTH1納米顆粒包含產生單線態(tài)氧(1O2)的MOF結構，通過可切割的10o2連接物與CRISPR-Cas9系統(tǒng)錨定，不僅作為靶向MTH1的CRISPR-Cas9的傳遞載體，而且作為時空激活基因組編輯的聲調節(jié)因子。P/M@CasMTH1從溶酶體中逃逸，獲取超聲(US)能量，并將其轉化為豐富的1O2誘導SDT。產生的ROS隨后觸發(fā)ROS響應的硫醚鍵的切割，從而誘導CRISPR-Cas9系統(tǒng)的可控釋放和基因組編輯的啟動。MTH1的基因組破壞通過破壞腫瘤細胞的自我防御系統(tǒng)，從而導致細胞凋亡和腫瘤抑制，顯著增強了SDT的治療效果。這種協同MTH1破壞和豐富的1O2生成的治療策略為基于新興的納米醫(yī)學基因組編輯技術增強SDT療效提供了一個范例。
