Zhao Yun, Li Ruomeng, Sun Junlin, Zou Zhiqiao, Wang Fuan, Liu Xiaoqing
College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, P.R. China.
ACS Nano. 2022 Apr 26;16(4):5404-5417. doi: 10.1021/acsnano.1c09008. Epub 2022 Apr 6.
High mortality and rapid development of metastasis requires the development of more effective antimetastasis strategies. However, conventional therapeutic methods, including surgery, radiation therapy, and chemotherapy, show less effectiveness in curbing the metastatic spread of cancer cells and the formation of metastases. A therapeutic platform, targeting the early stage of metastasis cascade, could effectively prevent metastasis dissemination. Herein, Fe/Mn-based metal-organic frameworks (FMM) were constructed for the delivery of a specific DNAzyme with high catalytic cleavage activity on the metastasis-involved Twist mRNA, thus efficiently inhibiting the invasion of cancer cells through DNAzyme-catalyzed gene silencing. Highly potent combined gene/chemodynamic therapy is achieved from the self-supplied DNAzyme cofactors and efficient glutathione depletion. Importantly, by virtue of the intrinsic photo-to-thermal conversion of the FMM nanocarriers, our combined therapeutic strategy could be further promoted under photothermal stimuli to speed up the Fenton reaction and to accelerate the release of the Twist DNAzyme with efficient gene therapy. Consequently, the effective elimination of tumors and the blockage of metastasis are simultaneously achieved under photothermal/magnetic resonance imaging guidance. This work aims at developing versatile theranostic agents to combat metastatic tumors.
高死亡率和转移的快速发展需要开发更有效的抗转移策略。然而，包括手术、放射治疗和化疗在内的传统治疗方法在抑制癌细胞的转移扩散和转移灶形成方面效果较差。一个针对转移级联早期阶段的治疗平台可以有效防止转移扩散。在此，构建了基于铁/锰的金属有机框架（FMM），用于递送对参与转移的Twist mRNA具有高催化切割活性的特定脱氧核酶，从而通过脱氧核酶催化的基因沉默有效抑制癌细胞的侵袭。通过自供应的脱氧核酶辅因子和有效的谷胱甘肽消耗实现了高效的联合基因/化学动力学治疗。重要的是，凭借FMM纳米载体的固有光热转换特性，我们的联合治疗策略可以在光热刺激下进一步促进，以加速芬顿反应并加速Twist脱氧核酶的释放，实现高效的基因治疗。因此，在光热/磁共振成像引导下，可同时有效消除肿瘤并阻断转移。这项工作旨在开发多功能的诊疗试剂来对抗转移性肿瘤。
