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

• 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
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2017.09.013

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]