College of Materials Science and Engineering, Qingdao University, Qingdao 266071, China.
College of Chemistry and Chemical Engineering, Key Laboratory of Shandong Provincial Universities for Functional Molecules and Materials, Qingdao University, Qingdao 266071, China.
ACS Nano. 2023 Jul 25;17(14):13533-13544. doi: 10.1021/acsnano.3c02009. Epub 2023 Jul 17.
Rational design of multifunctional nanomedicines has revolutionized the therapeutic efficacy of cancers. Herein, we have constructed the functional nucleic acids (FNAs)-engineered nanoplatforms based on the concept of a bio-barcode (BBC) for synergistic targeted therapy of multidrug-resistant (MDR) cancer. In this study, the platinum(IV) prodrug is synthesized to covalently link two kinds of FNAs at a rational ratio to fabricate three-dimensional BBC-like DNA nanoscaffolds, accompanied by the one-pot encapsulation of ZnO nanoparticles (NPs) through electrostatic interaction. The multivalent AS1411 aptamers equipped in ZnO@BBCs facilitate specific and efficient endocytosis into MDR human lung adenocarcinoma cells (A549/DDP). In response to the intracellular environment of A549/DDP cells, such as the lysosome-acidic pH and overexpressed GSH, the ZnO NPs are degraded into Zn ions for generating reactive oxygen species (ROS), while the Pt(IV) prodrugs are reduced into Pt(II) active species by glutathione (GSH), followed by the release of therapeutic DNAzymes for chemotherapy and gene therapy. In particular, the designed system plays an important role in remodeling the intracellular environment to reverse cancer MDR. On the one hand, the depletion of GSH promotes the downregulation of glutathione peroxidase 4 (GPX4) for amplifying oxidative stress and increasing lipid peroxidation (LPO), resulting in the activation of ferroptosis. On the other hand, the silence of early growth response protein 1 (Egr-1) mRNA by Zn-dependent DNAzymes directly inhibits the proliferation and migration of MDR cells, which further suppresses the P-glycoprotein (P-gp)-mediated drug efflux. Thus, the proposed nanoplatforms show great promise for the development of versatile therapeutic tools and personalized nanomedicines for MDR cancers.
基于生物条码（BBC）概念，构建了功能核酸（FNAs）工程化的纳米平台，用于协同治疗多药耐药（MDR）癌症。在这项研究中，合成了顺铂（IV）前药，以合理的比例将两种 FNAs 共价连接，构建了三维 BBC 样 DNA 纳米支架，并通过静电相互作用将 ZnO 纳米颗粒（NPs）一锅包封。多价 AS1411 适体装备在 ZnO@BBC 上，有利于 MDR 人肺腺癌细胞（A549/DDP）的特异性和高效内吞。针对 A549/DDP 细胞的细胞内环境，如溶酶体酸性 pH 和过表达的 GSH，ZnO NPs 降解为 Zn 离子，产生活性氧（ROS），而顺铂（IV）前药被 GSH 还原为 Pt(II) 活性物质，随后释放治疗性 DNA 酶进行化疗和基因治疗。特别是，所设计的系统在重塑细胞内环境以逆转癌症 MDR 方面发挥了重要作用。一方面，GSH 的耗竭促进了谷胱甘肽过氧化物酶 4（GPX4）的下调，以放大氧化应激和增加脂质过氧化（LPO），导致铁死亡的激活。另一方面，Zn 依赖性 DNA 酶对早期生长反应蛋白 1（Egr-1）mRNA 的沉默直接抑制 MDR 细胞的增殖和迁移，从而进一步抑制 P-糖蛋白（P-gp）介导的药物外排。因此，所提出的纳米平台为开发多功能治疗工具和个性化 MDR 癌症纳米药物提供了广阔的前景。
