胰腺癌是死亡率最高的恶性肿瘤之一，目前缺乏有效的治疗药物。适配体药物偶联物（ApDC）作为核酸药物的一种形式，在癌症治疗中显示出巨大的潜力。然而，核酸药物在体内的不稳定性以及间质致密的胰腺癌的无血管性限制了其应用。幸运的是，VNP20009是鼠伤寒沙门氏菌的一种转基因菌株，它偏爱厌氧环境，但有毒且缺乏特异性，有可能作为ApDC的递送载体。在这里，我们提出了一种协同治疗方法，通过简单的一步点击化学将 ApDC 与 VNP20009 结合，将细菌的渗透能力与 ApDC 的靶向和毒性作用结合起来。通过这种策略，细菌通过厌氧趋化作用特异性靶向胰腺癌，随后在适体的特异性结合驱动下粘附到肿瘤细胞上。结果表明，与游离药物组相比，该方法将 ApDC 的血清稳定性延长至 48 小时，并导致肿瘤部位的药物浓度增加。此外，适体与癌细胞的靶向结合使肿瘤部位的细菌定植增加了三倍，导致肿瘤细胞死亡和 T 细胞浸润增加。值得注意的是，通过整合化疗和免疫疗法，治疗效果显着增强，在各种动物模型中显示出一致的结果。总体而言，该策略利用了细菌和 ApDC，从而为胰腺癌治疗提供了一种有效的协同策略。© 2024。作者。

Pancreatic cancer is one of the most malignant tumors with the highest mortality rates, and it currently lacks effective drugs. Aptamer-drug conjugates (ApDC), as a form of nucleic acid drug, show great potential in cancer therapy. However, the instability of nucleic acid-based drugs in vivo and the avascularity of pancreatic cancer with dense stroma have limited their application. Fortunately, VNP20009, a genetically modified strain of Salmonella typhimurium, which has a preference for anaerobic environments, but is toxic and lacks specificity, can potentially serve as a delivery vehicle for ApDC. Here, we propose a synergistic therapy approach that combines the penetrative capability of bacteria with the targeting and toxic effects of ApDC by conjugating ApDC to VNP20009 through straightforward, one-step click chemistry. With this strategy, bacteria specifically target pancreatic cancer through anaerobic chemotaxis and subsequently adhere to tumor cells driven by the aptamer's specific binding. Results indicate that this method prolongs the serum stability of ApDC up to 48 h and resulted in increased drug concentration at tumor sites compared to the free drugs group. Moreover, the aptamer's targeted binding to cancer cells tripled bacterial colonization at the tumor site, leading to increased death of tumor cells and T cell infiltration. Notably, by integrating chemotherapy and immunotherapy, the effectiveness of the treatment is significantly enhanced, showing consistent results across various animal models. Overall, this strategy takes advantage of bacteria and ApDC and thus presents an effective synergistic strategy for pancreatic cancer treatment.© 2024. The Author(s).