Kejun Dong, Hao Hu, Shuangshuang Cheng, Yaoqin Mu, Wei Zhang, Ting Zhou, Jiarui Zhang, Wan Shu, Xiaoyu Shen, Hongbo Wang, Xianjin Xiao
Department of Obstetrics and Gynecology, Union Hospital and Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Department of Obstetrics and Gynecology, Union Hospital and Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Clinical Research Center of Cancer Immunotherapy of Hubei, Wuhan 430022, China.
J Control Release. 2025 Jun 10;382:113663. doi: 10.1016/j.jconrel.2025.113663. Epub 2025 Mar 28.
The inefficacy of chemotherapy in ovarian cancer, hindered by poor targeting and multiple drug resistance, is intricately linked to the tumor micro-environment and abnormal metabolic patterns. Here, we present ZnO@DS-DOX, an innovative nanomaterial that integrates small-sized ZnO nanoparticles with oxygen vacancies, embedded within 2D-ZnMOF and encapsulated in a DNA nanosponge, to enhance doxorubicin delivery. This system targets ovarian cancer cells specifically through the MUC1 aptamer and remodels metabolic signaling within the tumor microenvironment. ZnO alleviates hypoxia and reduces chemoresistance by catalyzing HO, while Zn release activates DNAzymes to target HIF-1a mRNA. The system reduces the efflux of chemotherapy drugs and inhibits cellular glycolysis. Disrupting the Warburg effect enhances mitochondrial respiration, increases ROS levels, disrupts the redox system, and induces ferroptosis, thereby significantly improving therapeutic efficacy. The uptake rate of ovarian cancer cells for the system was nearly 15 times higher than that of normal cells. Following treatment, the IC50 value of ovarian cancer cells decreased by approximately 72.7 %. Our in vitro and in vivo studies demonstrate that ZnO@DS-DOX effectively modulates tumor metabolic pathways, mitigates drug resistance, and enhances treatment outcomes, representing a significant advancement in nanomedicine and cancer therapy.
化疗在卵巢癌治疗中效果不佳，受到靶向性差和多重耐药性的阻碍，这与肿瘤微环境和异常代谢模式密切相关。在此，我们展示了ZnO@DS-DOX，一种创新的纳米材料，它将具有氧空位的小尺寸ZnO纳米颗粒整合到二维ZnMOF中，并封装在DNA纳米海绵中，以增强阿霉素的递送。该系统通过MUC1适配体特异性靶向卵巢癌细胞，并重塑肿瘤微环境中的代谢信号。ZnO通过催化HO缓解缺氧并降低化疗耐药性，而锌的释放激活DNA酶以靶向HIF-1a mRNA。该系统减少化疗药物的外排并抑制细胞糖酵解。破坏瓦伯格效应可增强线粒体呼吸、增加ROS水平、破坏氧化还原系统并诱导铁死亡，从而显著提高治疗效果。该系统对卵巢癌细胞的摄取率比正常细胞高出近15倍。治疗后，卵巢癌细胞的IC50值下降了约72.7%。我们的体外和体内研究表明，ZnO@DS-DOX有效地调节肿瘤代谢途径，减轻耐药性并提高治疗效果，代表了纳米医学和癌症治疗的重大进展。
