Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor in adults and despite advances in neuro-oncology, the prognosis for patients remains dismal. The signal transducer and activator of transcription-3 (STAT3) has been reported as key regulator of the highly aggressive mesenchymal glioblastoma subtype and its direct silencing (by RNAi oligonucleotides) has revealed a great potential as anti-cancer therapy. However, clinical use of oligonucleotide-based therapies is dependent on safer ways for tissue-specific targeting and increased membrane penetration. Objective of this study is to explore the use of nucleic acid aptamers as carriers to specifically drive a STAT3 siRNA to GBM cells in a receptor-dependent manner. Using an aptamer that binds to and antagonizes the oncogenic receptor tyrosine kinase PDGFRβ (Gint4.T), here we describe the design of a novel aptamer-siRNA chimera (Gint4.T-STAT3) to target STAT3. We demonstrate the efficient delivery and silencing of STAT3 in PDGFRβ positive GBM cells. Importantly, the conjugate reduces cell viability and migration in vitro and inhibits tumor growth and angiogenesis in vivo in a subcutaneous xenograft mouse model. Our data reveals Gint4.T-STAT3 conjugate as a novel molecule with great translational potential for GBM therapy.

胶质母细胞瘤（GBM）是成人中最常见，最具侵略性的原发性脑肿瘤，尽管神经肿瘤学有所进步，但患者的预后仍然令人沮丧。据报道，信号转导和转录激活因子3（STAT3）是高度侵袭性间充质胶质母细胞瘤亚型的关键调节剂，其直接沉默（通过RNAi寡核苷酸）已显示出作为抗癌疗法的巨大潜力。然而，基于寡核苷酸的疗法的临床应用取决于组织特异性靶向和增加膜渗透的更安全方法。这项研究的目的是探索使用核酸适体作为载体，以受体依赖的方式特异性地将STAT3 siRNA驱动到GBM细胞。使用能与致癌受体酪氨酸激酶PDGFRβ（Gint4.T）结合并拮抗的适体，在这里，我们描述了靶向STAT3的新型适体-siRNA嵌合体（Gint4.T-STAT3）的设计。我们证明了PDGFRβ阳性GBM细胞中STAT3的有效传递和沉默。重要的是，缀合物会降低细胞活力和迁移在体外和抑制肿瘤生长和血管生成在体内在皮下异种移植物小鼠模型。我们的数据显示Gint4.T-STAT3偶联物是一种新型分子，对GBM治疗具有巨大的翻译潜力。