He Cong, Jaffar Ali Doulathunnisa, Li Yumin, Zhu Yanliang, Sun Bo, Xiao Zhongdang
State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu, China.
Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, Jiangsu, China.
PeerJ. 2020 Jul 20;8:e9524. doi: 10.7717/peerj.9524. eCollection 2020.
Safe, efficient and cancer cell targeted delivery of CRISPR/Cas9 is important to increase the effectiveness of available cancer treatments. Although cancer derived exosomes offer significant advantages, the fact that it carries cancer related/inducing signaling molecules impedes them from being used as a reliable drug delivery vehicle. In this study, we report that normal epithelial cell-derived exosomes engineered to have HN3 (HN3LC9-293exo), target tumor cells as efficiently as that of the cancer cell-derived exosomes (C9HuH-7exo). HN3LC9-293exo were quickly absorbed by the recipient cancer cell in vitro. Anchoring HN3 to the membrane of the exosomes using LAMP2, made HN3LC9-293exo to specifically enter the GPC3 HuH-7 cancer cells than the GPC3 LO2 cells in a co-culture model. Further, sgIQ 1.1 plasmids were loaded to exosomes and surprisingly, in combination with sorafenib, synergistic anti-proliferative and apoptotic effect of loaded HN3LC9-293exo was more than the loaded C9HuH-7exo. While cancer-derived exosomes might induce the drug resistance and tumor progression, normal HEK-293 cells-derived exosomes with modifications for precise cancer cell targeting like HN3LC9-293exo can act as better, safe and natural delivery systems to improve the efficacy of the cancer treatments.
安全、高效且靶向癌细胞递送CRISPR/Cas9对于提高现有癌症治疗的有效性至关重要。尽管源自癌症的外泌体具有显著优势，但它携带癌症相关/诱导信号分子这一事实阻碍了它们被用作可靠的药物递送载体。在本研究中，我们报告经工程改造具有HN3的正常上皮细胞衍生的外泌体（HN3LC9 - 293exo）靶向肿瘤细胞的效率与癌细胞衍生的外泌体（C9HuH - 7exo）一样高。HN3LC9 - 293exo在体外能被受体癌细胞快速吸收。利用LAMP2将HN3锚定在外泌体膜上，使得在共培养模型中，HN3LC9 - 293exo比GPC3 LO2细胞更能特异性地进入GPC3 HuH - 7癌细胞。此外，将sgIQ 1.1质粒装载到外泌体中，令人惊讶的是，与索拉非尼联合使用时，装载的HN3LC9 - 293exo的协同抗增殖和凋亡作用比装载的C9HuH - 7exo更强。虽然源自癌症的外泌体可能诱导耐药性和肿瘤进展，但经过修饰以精确靶向癌细胞的正常HEK - 293细胞衍生的外泌体，如HN3LC9 - 293exo，可以作为更好、安全且天然的递送系统来提高癌症治疗的疗效。
