Sono‐Controllable and ROS‐Sensitive CRISPR‐Cas9 Genome Editing for Augmented/Synergistic Ultrasound Tumor Nanotherapy

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 o...

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Vydáno v:	Advanced materials (Weinheim) Ročník 33; číslo 45; s. e2104641 - n/a
Hlavní autoři:	Pu, Yinying, Yin, Haohao, Dong, Caihong, Xiang, Huijing, Wu, Wencheng, Zhou, Bangguo, Du, Dou, Chen, Yu, Xu, Huixiong
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	Germany Wiley Subscription Services, Inc 01.11.2021
Témata:	Animals Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Apoptosis Cell Line, Tumor Cell Survival - drug effects CRISPR CRISPR-Cas Systems - genetics Disruption DNA Repair Enzymes - genetics DNA Repair Enzymes - metabolism Editing Gene Editing - methods Genomes genomic editing Humans Lysosomes Materials science Metal-organic frameworks Metal-Organic Frameworks - chemistry Mice Mice, Nude Nanoparticles Nanoparticles - chemistry Neoplasms - pathology Neoplasms - therapy Phosphoric Monoester Hydrolases - genetics Phosphoric Monoester Hydrolases - metabolism Polymers - chemistry Porphyrins - chemistry Reactive Oxygen Species - metabolism RNA, Guide, CRISPR-Cas Systems - chemistry RNA, Guide, CRISPR-Cas Systems - metabolism ROS responsive Singlet oxygen sonodynamic therapy Transplantation, Heterologous tumor therapy Tumors Ultrasonic imaging Ultrasonic Therapy - methods sonodynamic therapy ROS responsive tumor therapy genomic editing metal-organic frameworks
ISSN:	0935-9648, 1521-4095, 1521-4095
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Shrnutí:	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. A novel avenue to circumvent the resistance of tumor cells in conventional sonodynamic therapy is pioneered in this work, where targeted delivery and controllable release of the cluster regularly interspaced short palindromic repeat‐associated protein system is also achieved.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0935-9648 1521-4095 1521-4095
DOI:	10.1002/adma.202104641