雄激素剥夺疗法一直是晚期前列腺癌（PCa）的主要治疗策略。但随着时间的推移，大多数患者会出现去势抵抗。对于 FDA 批准的第二代雄激素受体 (AR) 拮抗剂，包括恩杂鲁胺 (ENZ) 和阿比特龙 (AA)，最初对其产生反应的患者最终会产生耐药性。 ENZ/AA 抗性的关键机制涉及 AR 剪接变体 (AR-V)，特别是 AR-V7。目前的 AR 拮抗剂不能靶向 AR-V7，因为它缺乏 C 端配体结合结构域 (LBD)，但保留了 AR N 端结构域 (NTD)，但仍能激活雄激素反应基因。因此，针对 AR NTD 和 AR-V7 对于克服 ENZ 耐药性至关重要。不幸的是，由于难以定义其三维（3D）结构，AR NTD 被认为是“不可成药”的目标。在这种情况下，siRNA 非常适合解决这种不可成药的靶点。然而，siRNA不能自由扩散到细胞中，需要载体。在这方面，基于核酸的适体非常适合细胞类型特异性的体内siRNA递送。在这项研究中，我们开发了一种血清稳定的二价前列腺特异性膜抗原（PSMA）适体-AR-V7 siRNA嵌合体（PAP）。结果表明，PAP 可以敲低表达 PSMA 的去势抵抗细胞中的 AR 全长和 AR-V7。它可以使细胞系和 PCa 异种移植物中的 ENZ 重新敏感。 ENZ联合PAP可以显着抑制小鼠22Rv1异种移植物的生长，而无需经历去势。由于毒性低，PAP 有潜力为当前 ENZ 耐药的 PCa 提供新的抗雄激素治疗。

Androgen deprivation therapy has been the primary treatment strategy for advanced prostate cancer (PCa). But most patients develop castration resistance over time. For FDA-approved second-generation androgen receptor (AR) antagonists, including enzalutamide (ENZ) and abiraterone (AA), patients who initially respond to them eventually develop resistance. The key mechanism for resistance to ENZ/AA involves AR splice variants (AR-Vs) and specifically AR-V7. Current AR antagonists cannot target AR-V7 due to its lack of the C-terminal ligand-binding domain (LBD) but keeping the AR N-terminal domain (NTD) which still can activate androgen-responsive genes. Therefore, targeting the AR NTD and AR-V7 is critically important to overcome ENZ resistance. Unfortunately, AR NTD has been considered an "undruggable" target due to the difficulty in defining its three-dimensional (3D) structure. In this context, siRNA is highly suitable to address this undruggable target. However, siRNA cannot freely diffuse into cells, and a carrier is needed. In this regard, nucleic acid-based aptamers are highly suitable for cell type-specific delivery of siRNA in vivo. In this study, we have developed a serum-stable bivalent prostate-specific membrane antigen (PSMA) aptamer-AR-V7 siRNA chimera (PAP). The results show that PAP can knock down both AR-full length and AR-V7 in PSMA-expressing castration-resistant cells. It can resensitize ENZ in cell lines and PCa xenografts. ENZ combined with PAP can significantly inhibit 22Rv1 xenograft growth in mice without experiencing castration. Owing to the low toxicity, PAP has potential to offer a new antiandrogen treatment for current ENZ-resistant PCa.