Codelivery of CRISPR-Cas9 and chlorin e6 for spatially controlled tumor-specific gene editing with synergistic drug effects

Controlled release of CRISPR-Cas9 ribonucleoprotein (RNP) and codelivery with other drugs remain a challenge. We demonstrate controlled release of CRISPR-Cas9 RNP and codelivery with antitumor photosensitizer chlorin e6 (Ce6) using near-infrared (NIR)- and reducing agent-responsive nanoparticles in...

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Bibliographic Details
Published in:Science advances 2020-07, Vol.6 (29), p.eabb4005
Main Authors: Deng, Shaohui, Li, Xiaoxia, Liu, Shuang, Chen, Jifeng, Li, Mingqiang, Chew, Sing Yian, Leong, Kam W, Cheng, Du
Format: Article
Language:English
Subjects:
Animals
Cell Line, Tumor
Chlorophyllides
CRISPR-Cas Systems
Delayed-Action Preparations
Gene Editing
Health and Medicine
Materials Science
Mice
Nanoparticles
Neoplasms - genetics
NF-E2-Related Factor 2 - metabolism
Reactive Oxygen Species - metabolism
Ribonucleoproteins - genetics
RNA, Guide, CRISPR-Cas Systems
SciAdv r-articles
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Summary:Controlled release of CRISPR-Cas9 ribonucleoprotein (RNP) and codelivery with other drugs remain a challenge. We demonstrate controlled release of CRISPR-Cas9 RNP and codelivery with antitumor photosensitizer chlorin e6 (Ce6) using near-infrared (NIR)- and reducing agent-responsive nanoparticles in a mouse tumor model. Nitrilotriacetic acid-decorated micelles can bind His-tagged Cas9 RNP. Lysosomal escape of nanoparticles was triggered by NIR-induced reactive oxygen species (ROS) generation by Ce6 in tumor cells. Cytoplasmic release of Cas9/single-guide RNA (sgRNA) was achieved by reduction of disulfide bond. Cas9/sgRNA targeted the antioxidant regulator , enhancing tumor cell sensitivity to ROS. Without NIR irradiation, Cas9 was degraded in lysosomes and gene editing failed in normal tissues. The synergistic effects of Ce6 photodynamic therapy and gene editing were confirmed in vivo. Controlled release of CRISPR-Cas9 RNP and codelivery with Ce6 using stimuli-responsive nanoparticles represent a versatile strategy for gene editing with potentially synergistic drug effects.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abb4005