Cancer-derived exosomes as a delivery platform of CRISPR/Cas9 confer cancer cell tropism-dependent targeting

An intracellular delivery system for CRISPR/Cas9 is crucial for its application as a therapeutic genome editing technology in a broad range of diseases. Current vehicles carrying CRISPR/Cas9 limit in vivo delivery because of low tolerance and immunogenicity; thus, the in vivo delivery of genome edit...

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Bibliographic Details
Published in:Journal of controlled release 2017-11, Vol.266, p.8-16
Main Authors: Kim, Seung Min, Yang, Yoosoo, Oh, Seung Ja, Hong, Yeonsun, Seo, Minkoo, Jang, Mihue
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - therapeutic use
Cancer therapy, combination therapy
Cell Line, Tumor
Cisplatin
Cisplatin - therapeutic use
Combined Modality Therapy
CRISPR-Cas Systems
CRISPR/Cas9
Cytokines - immunology
Delivery vehicle
Exosomes
Female
Gene editing
Gene Transfer Techniques
Genetic Therapy
HEK293 Cells
Humans
Leukocytes, Mononuclear - immunology
Mice, Inbred BALB C
Mice, Nude
Neoplasms - genetics
Neoplasms - pathology
Neoplasms - therapy
PARP-1
Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors
Poly (ADP-Ribose) Polymerase-1 - genetics
RNA - genetics
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Summary:An intracellular delivery system for CRISPR/Cas9 is crucial for its application as a therapeutic genome editing technology in a broad range of diseases. Current vehicles carrying CRISPR/Cas9 limit in vivo delivery because of low tolerance and immunogenicity; thus, the in vivo delivery of genome editing remains challenging. Here, we report that cancer-derived exosomes function as natural carriers that can efficiently deliver CRISPR/Cas9 plasmids to cancer. Compared to epithelial cell-derived exosomes, cancer-derived exosomes provide potential vehicles for effective in vivo delivery via selective accumulation in ovarian cancer tumors of SKOV3 xenograft mice, most likely because of their cell tropism. CRISPR/Cas9-loaded exosomes can suppress expression of poly (ADP-ribose) polymerase-1 (PARP-1), resulting in the induction of apoptosis in ovarian cancer. Furthermore, the inhibition of PARP-1 by CRISPR/Cas9-mediated genome editing enhances the chemosensitivity to cisplatin, showing synergistic cytotoxicity. Based on these results, tumor-derived exosomes may be very promising for cancer therapeutics in the future. Graphical abstract [Display omitted]
ISSN:0168-3659
1873-4995
DOI:10.1016/j.jconrel.2017.09.013