Cancer-derived exosomes as a delivery platform of CRISPR/Cas9 confer cancer cell tropism-dependent targeting
Cancer-derived exosomes as a delivery platform of CRISPR/Cas9 confer cancer cell tropism-dependent targeting
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DOI：
10.1016/j.jconrel.2017.09.013
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发表时间：
2017-11-28
影响因子：
10.8
通讯作者：
Jang, Mihue
中科院分区：
文献类型：
--
作者：
Kim, Seung Min;Yang, Yoosoo;Jang, Mihue
CRISPR/Cas9 的细胞内递送系统对于其作为治疗性基因组编辑技术在多种疾病中的应用至关重要。目前携带 CRISPR/Cas9 的载体由于耐受性和免疫原性低而限制了体内递送；因此，基因组编辑的体内传递仍然具有挑战性。在这里，我们报告癌症来源的外泌体作为天然载体，可以有效地将 CRISPR/Cas9 质粒传递到癌症。与上皮细胞来源的外泌体相比，癌症来源的外泌体通过选择性积累在 SKOV3 异种移植小鼠的卵巢癌肿瘤中，为有效体内递送提供了潜在的载体，这很可能是因为它们的细胞向性。装载 CRISPR/Cas9 的外泌体可以抑制聚（ADP-核糖）聚合酶-1（PARP-1）的表达，从而诱导卵巢癌细胞凋亡。此外，CRISPR/Cas9介导的基因组编辑对PARP-1的抑制增强了对顺铂的化学敏感性，表现出协同细胞毒性。基于这些结果，肿瘤来源的外泌体在未来的癌症治疗中可能非常有前景。
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.