CL4-modified exosomes deliver lncRNA DARS-AS1 siRNA to suppress triple-negative breast cancer progression and attenuate doxorubicin resistance by inhibiting autophagy

Xinli Liu; Ge Zhang; Tongyao Yu; Jie Liu; Xiaoxia Chai; Dachuan Yin; Chenyan Zhang

doi:10.1016/j.ijbiomac.2023.126147

CL4-modified exosomes deliver lncRNA DARS-AS1 siRNA to suppress triple-negative breast cancer progression and attenuate doxorubicin resistance by inhibiting autophagy

Int J Biol Macromol. 2023 Oct 1:250:126147. doi: 10.1016/j.ijbiomac.2023.126147. Epub 2023 Aug 5.

Authors

Xinli Liu¹, Ge Zhang¹, Tongyao Yu¹, Jie Liu¹, Xiaoxia Chai¹, Dachuan Yin², Chenyan Zhang³

Affiliations

¹ Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, PR China.
² Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, PR China. Electronic address: yindc@nwpu.edu.cn.
³ Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, PR China. Electronic address: zhangchenyan@nwpu.edu.cn.

PMID: 37544559
DOI: 10.1016/j.ijbiomac.2023.126147

Abstract

Triple-negative breast cancer (TNBC) is a fatal disease. Drug resistance and the lack of effective drugs are the leading causes of death in patients with TNBC. Recently, long non-coding RNAs have been proven to be effective drug design targets owing to their high tissue specificity; however, an effective drug delivery system is necessary for their clinical application. In this study, we constructed a novel nanodrug delivery system based on the epidermal growth factor receptor (EGFR)-targeted aptamer CL4-modified exosomes (EXOs-CL4) for the targeted delivery of aspartyl-tRNA synthetase-antisense RNA 1 (DARS-AS1) small interfering RNA (siRNA) and doxorubicin (DOX) to TNBC cells in vitro and in vivo. This delivery system exerted potent anti-proliferation, anti-migration, and pro-apoptotic effects on TNBC cells. Silencing DARS-AS1 increased the sensitivity of TNBC cells to DOX by suppressing the transforming growth factor-β (TGF-β)/Smad3 signaling pathway-induced autophagy, thereby enhancing the synergetic antitumor effects. Collectively, our findings revealed that EXOs-CL4-mediated delivery of DARS-AS1 siRNA can be used as a new treatment strategy for DOX-resistant TNBC. Moreover, EXOs-CL4 can be used as effective drug delivery systems for targeted TNBC therapy.

Keywords: Autophagy; CL4-modified exosomes (EXOs-CL4); Chemosensitivity; Exosome (EXOs); Triple-negative breast cancer (TNBC).