三阴性乳腺癌（TNBC）是最致命的乳腺癌亚型。缺氧激活的前药（HAP）已显示出有望作为TNBC的潜在治疗剂。虽然增加缺氧水平可能会促进HAP的激活，它引起了人们对HIF1α依赖性耐药性的担忧。期望开发一种靶向方法,其增强肿瘤缺氧以激活HAP而不促进TNBC治疗中的HIF1α依赖性药物抗性。在这里，提出了一种多响应无载体自组装纳米药物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性和酸性条件下分解。释放的Combrestatin4（CA4）可以加剧缺氧，从而促进无活性的Banoxantrone（AQ4N）向其活性形式的转化，AQ4.同时,所释放的反义寡核苷酸(ASO)可以减弱缺氧诱导的HIF1αmRNA表达,从而使肿瘤对化疗敏感。总的来说,这种智能纳米医学代表了一种深刻的靶向治疗策略，结合“增强缺氧，缺氧激活，TNBC治疗的化学致敏方法。体内研究证明了肿瘤生长的显著抑制，强调了这种纳米医学在未来临床翻译中的有希望的潜力。
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.
