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Designer Exosomes for Targeted Delivery of a Novel Therapeutic Cargo to Enhance Sorafenib-Mediated Ferroptosis in Hepatocellular Carcinoma

Authors :
Xiaoju Li
Qianqian Yu
Runze Zhao
Xinyan Guo
Chenlin Liu
Kuo Zhang
Wangqian Zhang
Jinghan Liu
Jinzheng Yu
Shuning Wang
Qiang Hao
Weina Li
Wei Zhang
Meng Li
Yingqi Zhang
Cun Zhang
Yuan Gao
Source :
Frontiers in Oncology, Vol 12 (2022)
Publication Year :
2022
Publisher :
Frontiers Media S.A., 2022.

Abstract

Sorafenib is one of the few effective first-line drugs approved for the treatment of advanced hepatocellular carcinoma (HCC). However, the development of drug resistance is common among individuals with HCC. Recent evidence indicated that the anticancer activity of sorafenib mainly relies on the induction of ferroptosis. Furthermore, in our study, genes that suppress ferroptosis, especially GPX4 and DHODH, were enriched in sorafenib-resistant cells and primary tissues and were associated with poor prognosis of HCC patients who received sorafenib treatment. Therefore, a new ferroptosis inducer comprising a multiplex small interfering RNA (multi-siRNA) capable of simultaneously silencing GPX4 and DHODH was created. Then, exosomes with high multi-siRNA loading and HCC-specific targeting were established by fusing the SP94 peptide and the N-terminal RNA recognition motif (RRM) of U1-A with the exosomal membrane protein Lamp2b. The results from the in vitro and in vivo experiments indicate that this tumor-targeting nano-delivery system (ExoSP94-lamp2b-RRM-multi-siRNA) could enhance sorafenib-induced ferroptosis and overcome sorafenib resistance. Taken together, HCC-targeted exosomes (ExoSP94-Lamp2b-RRM) could specifically deliver multi-siRNA to HCC tissues, enhance sorafenib-induced ferroptosis by silencing GPX4 and DHODH expression and consequently increase HCC sensitivity to sorafenib, which opens a new avenue for clinically overcoming sorafenib resistance from the perspective of ferroptosis.

Details

Language :
English
ISSN :
2234943X
Volume :
12
Database :
Directory of Open Access Journals
Journal :
Frontiers in Oncology
Publication Type :
Academic Journal
Accession number :
edsdoj.75d4b8f6a1c748aab601f86d2bc6cd24
Document Type :
article
Full Text :
https://doi.org/10.3389/fonc.2022.898156