清脆的
基因组编辑
Cas9
单线态氧
基因组
计算生物学
纳米医学
活性氧
生物
细胞生物学
化学
纳米技术
材料科学
基因
生物化学
纳米颗粒
有机化学
氧气
作者
Yinying Pu,Haohao Yin,Caihong Dong,Huijing Xiang,Wei Wu,Baowen Zhou,Dou Du,Yu Chen,Hui‐Xiong Xu
标识
DOI:10.1002/adma.202104641
摘要
Abstract 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 ( 1 O 2 )‐generating MOF structures anchored with CRISPR‐Cas9 systems via 1 O 2 ‐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 1 O 2 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 1 O 2 generation provides a paradigm for augmenting SDT efficacy based on the emerging nanomedicine‐enabled genome‐editing technology.
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