The combination of chemotherapy and gene therapy holds great promise for the treatment and eradication of tumors. However, due to significant differences in physicochemical properties between chemotherapeutic agents and functional nucleic acid drugs, direct integration into a single nano-agent is hindered, impeding the design and construction of an effective co-delivery nano-platform for synergistic anti-tumor treatments. In this study, we have developed an mRNA-responsive two-in-one nano-drug for effective anti-tumor therapy by the direct self-assembly of 2′-fluoro-substituted antisense DNA against P-glycoprotein (2′F-DNA) and chemo drug paclitaxel (PTX). The 2′-fluoro modification of DNA could significantly increase the interaction between the therapeutic nucleic acid and the chemotherapeutic drug, promoting the successful formation of 2′F-DNA/PTX nanospheres (2′F-DNA/PTX NSs). Due to the one-step self-assembly process without additional carrier materials, the prepared 2′F-DNA/PTX NSs exhibited considerable loading efficiency and bioavailability of PTX. In the presence of endogenous P-glycoprotein mRNA, the 2′F-DNA/PTX NSs were disassembled. The released 2′F-DNA could down-regulate the expression of P-glycoprotein, which decreased the multidrug resistance of tumor cells and enhanced the chemotherapy effect caused by PTX. In this way, the 2′F-DNA/PTX NSs could synergistically induce the apoptosis of tumor cells and realize the combined anti-tumor therapy. This strategy might provide a new tool to explore functional intracellular co-delivery nano-systems with high bioavailability and exhibit potential promising in the applications of accurate diagnosis and treatment of tumors.

中文翻译：

---

用于增强抗肿瘤化学基因治疗的 mRNA 响应二合一纳米药物


化疗和基因疗法的结合为治疗和根除肿瘤带来了巨大的希望。然而，由于化疗药物和功能性核酸药物之间的理化性质存在显着差异，直接整合到单一纳米药物中受到阻碍，从而阻碍了用于协同抗肿瘤治疗的有效共递送纳米平台的设计和构建。在这项研究中，我们通过直接自组装针对P-糖蛋白（2'F-DNA）的2'-氟取代反义DNA，开发了一种mRNA响应的二合一纳米药物，用于有效的抗肿瘤治疗。 ）和化疗药物紫杉醇（PTX）。 DNA的2'-氟修饰可以显着增加治疗核酸与化疗药物之间的相互作用，促进2'F-DNA/PTX纳米球（2'F-DNA/PTX NSs）的成功形成。由于一步自组装过程无需额外的载体材料，所制备的2'F-DNA/PTX NSs表现出相当大的PTX负载效率和生物利用度。在内源性 P-糖蛋白 mRNA 存在的情况下，2'F-DNA/PTX NS 被分解。释放的2′F-DNA可下调P-糖蛋白的表达，从而降低肿瘤细胞的多药耐药性，增强PTX的化疗效果。这样，2'F-DNA/PTX NSs可以协同诱导肿瘤细胞凋亡，实现联合抗肿瘤治疗。该策略可能为探索具有高生物利用度的功能性细胞内共递送纳米系统提供新工具，并在肿瘤准确诊断和治疗的应用中表现出潜在的应用前景。