三阴性乳腺癌（TNBC）是乳腺癌中最致命的亚型。缺氧激活前药（HAP）已显示出作为 TNBC 潜在治疗剂的前景。虽然增加缺氧水平可能会促进 HAP 激活，但它引起了人们对 HIF1α 依赖性耐药性的担忧。在 TNBC 治疗中，需要开发一种靶向方法，在不促进 HIF1α 依赖性耐药性的情况下，增强肿瘤缺氧以促进 HAP 激活。在此，我们提出了一种多响应无载体自组装纳米药物，命名为AQ4N@CA4T1ASO。这种纳米药物首先通过 TNBC 靶向适体 (T1) 靶向肿瘤，然后在肿瘤内的还原和酸性条件下分解。释放的 Combretastatin 4 (CA4) 可能会加剧缺氧，从而促进无活性的 Banoxantrone (AQ4N) 转化为其活性形式 AQ4。同时，释放的反义寡核苷酸（ASO）可以减弱缺氧诱导的 HIF1α mRNA 表达，从而使肿瘤对化疗敏感。总体而言，这种智能纳米药物代表了一种意义深远的靶向治疗策略，结合了“缺氧增强、缺氧激活、化疗增敏”的 TNBC 治疗方法。体内研究证明可显着抑制肿瘤生长，凸显了这种纳米药物在未来临床转化方面的巨大潜力。版权所有 © 2024。由 Elsevier B.V. 出版。

Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer. Hypoxia-activated prodrugs (HAPs) have shown promise as potential therapeutic agents for TNBC. While increasing hypoxia levels may promote the HAP activation, it raises concerns regarding HIF1α-dependent drug resistance. It is desirable to develop a targeted approach that enhances tumor hypoxia for HAP activation without promoting HIF1α-dependent drug resistance in TNBC treatment. Herein, we proposed a multi-responsive carrier-free self-assembled nanomedicine named AQ4N@CA4T1ASO. This nanomedicine first targeted tumors by the TNBC-targeting aptamers (T1), and then disassembled in the reductive and acidic conditions within tumors. The released Combretastatin 4 (CA4) could exacerbate hypoxia, thereby promoting the conversion of inactive Banoxantrone (AQ4N) to its active form, AQ4. Simultaneously, the released antisense oligonucleotide (ASO) could attenuate hypoxia-induced HIF1α mRNA expression, thereby sensitizing the tumor to chemotherapy. Overall, this smart nanomedicine represents a profound targeted therapy strategy, combining "hypoxia-potentiating, hypoxia-activated, chemo-sensitization" approaches for TNBC treatment. In vivo study demonstrated significant suppression of tumor growth, highlighting the promising potential of this nanomedicine for future clinical translation.Copyright © 2024. Published by Elsevier B.V.