三阴性乳腺癌（TNBC）是一种致命的疾病。药物耐药和缺乏有效药物是导致TNBC患者死亡的主要原因。最近，长非编码RNA已被证明是有效的药物设计靶点，因为它们具有高组织特异性。然而，临床应用必须配备有效的药物输送系统。本研究构建了一种新颖的基于表皮生长因子受体（EGFR）靶向寡核苷酸CL4修饰的外泌体（EXOs-CL4）纳米药物输送系统，用于体外和体内向TNBC细胞靶向输送天冬氨酰-tRNA合成酶抗义RNA 1（DARS-AS1）小干扰RNA（siRNA）和阿霉素（DOX）。该输送系统对TNBC细胞具有强效的抗增殖、抗迁移和促凋亡作用。沉默DARS-AS1通过抑制转化生长因子-β（TGF-β）/Smad3信号通路诱导的自噬，提高TNBC细胞对DOX的敏感性，从而增强协同抗肿瘤效应。综上所述，我们的研究结果揭示了EXOs-CL4介导的DARS-AS1 siRNA输送可作为DOX耐药TNBC的新治疗策略。此外，EXOs-CL4可用作靶向TNBC治疗的有效药物输送系统。版权所有© 2023年。由Elsevier B.V.出版。

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.Copyright © 2023. Published by Elsevier B.V.