Sun Huanhuan, Wang Tianzheng, Ma Wenjie, Huang Jin, Chen Biao, Cheng Hong, Duan Shuangdi, He Xiaoxiao, Jian Lixin, Wang Kemin
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Hunan University, Key Laboratory for Bio-Nanotechnology and Molecule Engineering of Hunan Province, Changsha, 410082, China.
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Hunan University, Key Laboratory for Bio-Nanotechnology and Molecule Engineering of Hunan Province, Changsha, 410082, China.
Biomaterials. 2022 Sep;288:121738. doi: 10.1016/j.biomaterials.2022.121738. Epub 2022 Aug 12.
Despite DNA nanotechnology has spawned a broad variety and taken a giant leap toward cancer theranostic applications over the last decade, the homogeneous DNA nanostructures often suffer from fatal degradation due to their limited stability and specificity. Herein, for the first time, we report a stable DNA tetrahedra-gold nanoclusters (DT/AuNCs) nanohybrid with a self-assembly/programmed disassembly manner for stimuli-responsive tumor imaging and gene-chemo therapy. By utilizing the multifunctional peptides with positive and legumain-specific domains as bioligands, AuNCs were synthesized as signal generators and gate guard attached on the dual-responsive DT, forming the DT/AuNCs with sequential response to legumain-TK1 mRNA & glutathione. The tumorous biomarker of legumain initiated the signal generation relying on the nanosurface energy transfer effect of AuNCs and denudation of DT-Dox (preliminary disassembly). Successively, the dual-responsive DT-Dox administrated a sequential fragmentation along with Dox release in response to the up-regulated glutathione and TK1 mRNA (secondary disassembly), thereby leading to combined gene silencing and chemo-therapy. The results revealed that the DT/AuNCs nanohybrids significantly improved the stability and enhanced the therapeutic efficiency compared to naked DT. Endowing with remarkable stability against biological milieu and site specificity for drug release, our work exhibits a new prospect of fabricating DNA-based nanohybrids for precise tumor theranostics.
尽管在过去十年中，DNA纳米技术已经产生了广泛的种类，并在癌症诊疗应用方面取得了巨大飞跃，但由于其稳定性和特异性有限，均相DNA纳米结构往往会遭受致命的降解。在此，我们首次报道了一种具有自组装/程序性拆卸方式的稳定DNA四面体-金纳米簇（DT/AuNCs）纳米杂化物，用于刺激响应性肿瘤成像和基因化疗。通过利用具有正性和天冬酰胺酶特异性结构域的多功能肽作为生物配体，将AuNCs合成为信号发生器和附着在双响应DT上的门控保护装置，形成对天冬酰胺酶-TK1 mRNA和谷胱甘肽具有顺序响应的DT/AuNCs。天冬酰胺酶的肿瘤生物标志物依靠AuNCs的纳米表面能量转移效应和DT-Dox的剥蚀（初步拆卸）启动信号产生。随后，双响应DT-Dox响应上调的谷胱甘肽和TK1 mRNA进行顺序片段化并释放Dox（二次拆卸），从而导致基因沉默和化疗联合进行。结果表明，与裸DT相比，DT/AuNCs纳米杂化物显著提高了稳定性并增强了治疗效果。我们的工作赋予了对生物环境的卓越稳定性和药物释放的位点特异性，展示了制造用于精确肿瘤诊疗的基于DNA的纳米杂化物的新前景。
