Eliminating the original cargos of glioblastoma cell-derived small extracellular vesicles for efficient drug delivery to glioblastoma with improved biosafety

Yuhang Guo; Guowen Hu; Yuguo Xia; HaiYan Li; Ji Yuan; Juntao Zhang; Yu Chen; Hua Guo; Yunlong Yang; Yang Wang; Zhifeng Deng

doi:10.1016/j.bioactmat.2022.02.013

Eliminating the original cargos of glioblastoma cell-derived small extracellular vesicles for efficient drug delivery to glioblastoma with improved biosafety

Bioact Mater. 2022 Mar 16:16:204-217. doi: 10.1016/j.bioactmat.2022.02.013. eCollection 2022 Oct.

Authors

Yuhang Guo¹, Guowen Hu^{1

2}, Yuguo Xia^{1

3}, HaiYan Li⁴, Ji Yuan⁵, Juntao Zhang⁵, Yu Chen⁵, Hua Guo², Yunlong Yang⁵, Yang Wang⁵, Zhifeng Deng¹

Affiliations

¹ Department of Neurosurgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, China.
² Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, 1# Minde Road, Nanchang, China.
³ Department of Neurosurgery, Xiangya Hospital Central South University, 87# Xiangya Road, Changsha, China.
⁴ Chemical and Environmental Engineering Department, School of Engineering, RMIT University, 124 La Trobe St, Melbourne VIC 3001, Australia.
⁵ Institute of Microsurgery on Extremities, Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600# Yishan Road, Shanghai, 200233, China.

Abstract

Tumor derived small extracellular vesicles (TsEVs) display a great potential as efficient nanocarriers for chemotherapy because of their intrinsic targeting ability. However, the inherited risks of their original cargos (like loaded proteins or RNAs) from parent cancer cells in tumor progression severely hinder the practical application. In this study, a saponin-mediated cargo elimination strategy was established and practiced in glioblastoma (GBM) cell-derived small extracellular vesicles (GBM-sEVs). A high eliminating efficacy of the cargo molecules was confirmed by systematic analysis of the original proteins and RNAs in GBM-sEVs. In addition, the inherited functions of GBM-sEVs to promote GBM progression vanished after saponin treatment. Moreover, the results of cellular uptake analysis and in vivo imaging analysis demonstrated that saponin treatment preserved the homotypic targeting ability of GBM-sEVs. Thus, we developed an efficient nanocarrier with improved biosafety for GBM suppression. Furthermore, doxorubicin (DOX) transported by the saponin-treated GBM-sEVs (sa-GBM-sEVs) displayed an effective tumor suppression in both subcutaneous and orthotopic GBM models of mouse. Collectively, this study provides a feasible way to avoid the potential protumoral risks of TsEVs and can advance the clinical application of TsEVs in chemotherapy.

Keywords: Cargo elimination; Drug delivery; Glioblastoma; Saponin; Tumor derived small extracellular vesicles.