通过加强的识别能力、细胞摄取能力和生物稳定性，使以寡核苷酸为基础的靶向抗癌试剂具备了显著特征，并可能与肿瘤部位的积累增加、治疗效果改善和负面副作用减少有关。在本文中，采用磷酸硫酯骨架修饰策略，调节胰腺癌细胞靶向寡核苷酸的生物医学性能，以实现高效的体内药物输送。具体而言，CD71靶向寡核苷酸XQ-2d被修饰成含有全硫取代的寡核苷酸S-XQ-2d，提高了S-XQ-2d及丝裂霉素C（MMC）功能化S-XQ-2d（MFSX）在小鼠体内的血浆稳定性，从而显著延长它们的半衰期。此外，S-XQ-2d的结合和摄入能力也得到了显著提高。MFSX表现出与MMC相当的细胞毒性水平，对非靶向细胞的毒性较低，突显出其特异性和生物安全性。简要的机制研究表明，XQ-2d和S-XQ-2d在与靶向细胞的相互作用模式和内化途径上存在差异。© 2023作者授权由中国科学出版传媒有限公司代表牛津大学出版社发表。

Enhanced recognition ability, cell uptake capacity, and biostability are characteristics attributed to aptamer-based targeted anticancer agents, and are possibly associated with increased accumulation at the tumor site, improved therapeutic efficacy and reduced negative side effects. Herein, a phosphorothioate backbone modification strategy was applied to regulate the biomedical properties of pancreatic cancer cell-targeting aptamer for efficient in vivo drug delivery. Specifically, the CD71- targeting aptamer XQ-2d was modified into a fully thio-substituted aptamer S-XQ-2d, improving the plasma stability of S-XQ-2d and mitomycin C (MMC)-functionalized S-XQ-2d (MFSX), thus considerably prolonging their half-life in mice. Moreover, the binding and uptake capacities of S-XQ-2d were significantly enhanced. MFSX showed the same level of cytotoxicity as that of MMC against targeted cancer cells, but lower toxicity to non-targeted cells, highlighting its specificity and biosafety. Brief mechanistic studies demonstrated that XQ-2d and S-XQ-2d had different interaction modes and internalization pathways with the targeted cells.© The Author(s) 2023. Published by Oxford University Press on behalf of China Science Publishing & Media Ltd.