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 Aug 4;126147. doi: 10.1016/j.ijbiomac.2023.126147.
Xinli Liu  1 ,  Ge Zhang  1 ,  Tongyao Yu  1 ,  Jie Liu  1 ,  Xiaoxia Chai  1 ,  Dachuan Yin  2 ,  Chenyan Zhang  3
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: [email protected].
  • 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: [email protected].
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).
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