Engineering of HN3 increases the tumor targeting specificity of exosomes and upgrade the anti-tumor effect of sorafenib on HuH-7 cells

Cong He; Doulathunnisa Jaffar Ali; Yumin Li; Yanliang Zhu; Bo Sun; Zhongdang Xiao

doi:10.7717/peerj.9524

Engineering of HN3 increases the tumor targeting specificity of exosomes and upgrade the anti-tumor effect of sorafenib on HuH-7 cells

PeerJ. 2020 Jul 20:8:e9524. doi: 10.7717/peerj.9524. eCollection 2020.

Authors

Cong He¹, Doulathunnisa Jaffar Ali^{1

2}, Yumin Li¹, Yanliang Zhu¹, Bo Sun¹, Zhongdang Xiao¹

Affiliations

¹ State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu, China.
² 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.

Abstract

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.

Keywords: Exosomes; GPC3; HEK-293; HN3; HuH-7; Sorafenib.

Grants and funding

This research was funded by Jiangsu Post-Doctoral Fund, grant number 1107030170, National Natural Science Foundation of China, grant number 81671807 and Fundamental Research Funds for the Central Universities, grand number 2242018K3DN05 and 2242017K40236. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.