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 Molecular Engineering of Hunan Province, Changsha 410082, China.
Theranostics. 2022 Apr 24;12(7):3474-3487. doi: 10.7150/thno.72028. eCollection 2022.
Static assembled multivalent DNA nanotheranostics system have encountered some bottleneck problems in cancer imaging and therapy, such as poor penetration and high immunogenicity. Herein, we proposed an acidic tumor microenvironment triggered assembly of activatable multivalent nanodevice, called "three-arm aptamer nanoclaw" (TA-aptNC), assembled from three pH-responsive aptamer-decorated DNA monomers (pH-aptDMs) to facilitate their functions of imaging and therapy.
The activated TA-aptNC was constructed by acidic microenvironment triggered assembly of three pH-aptDMs. Designer pH-aptDM was established based on the combination of a pH-responsive i-motif switch and an assembly module with a cell membrane anchoring aptamer ligand. Acidic microenvironment-triggered the assembly of the TA-aptNC was characterized by electrophoresis and atomic force microscopic (AFM). The binding affinity and stability of the TA-aptNC, comparing the monovalent pH-aptDM, were studied via the flow cytometry and nuclease resistance assays. Acidic microenvironment-activated contrast-enhanced tumor imaging and significantly antitumor efficiency were evaluated and . : At physiological pH environment, the pH-aptDMs with excellent tissue permeability exited as inactivated and monodispersed small monomer. When encountering acidic microenvironment at the tumor site, pH-responsive i-motif switch liberated from the pH-aptDMs, and the three unconstrained DNA modules (DM, DM and DM) subsequently assembled into the TA-aptNC. Compared with monovalent pH-aptDMs, the spontaneously formed activatable TA-aptNC afforded 2-fold enhanced binding ability via the multivalent effect, which further facilitated the selective tumor cell uptake capability, thus enabling a contrast-enhanced tumor imaging and significantly antitumor efficiency without systemic toxicity. : The proposed strategy offers valuable insight into excavating an endogenous stimuli-triggered assembly of multivalent nanodevice for accurate diagnosis and efficient tumor therapy.
静态组装的多价 DNA 纳米诊疗系统在癌症成像和治疗中遇到了一些瓶颈问题，例如穿透性差和免疫原性高。在此，我们提出了一种酸性肿瘤微环境触发的可激活多价纳米器件的组装，称为“三臂适体纳米爪”（TA-aptNC），由三个 pH 响应适体修饰的 DNA 单体（pH-aptDM）组装而成，以促进其成像和治疗功能。
通过酸性微环境触发三个 pH-aptDM 的组装来构建激活的 TA-aptNC。设计 pH-aptDM 是基于 pH 响应 i-motif 开关和具有细胞膜锚定适体配体的组装模块的组合建立的。通过电泳和原子力显微镜（AFM）对 TA-aptNC 的酸性微环境触发组装进行了表征。通过流式细胞术和核酸酶抗性实验研究了 TA-aptNC 的结合亲和力和稳定性，与单价 pH-aptDM 进行了比较。
在生理 pH 环境下，具有优异组织通透性的 pH-aptDM 以失活的和单分散的小单体形式存在。当在肿瘤部位遇到酸性微环境时，pH 响应 i-motif 开关从 pH-aptDM 中释放出来，三个未约束的 DNA 模块（DM、DM 和 DM）随后组装成 TA-aptNC。与单价 pH-aptDM 相比，自发形成的可激活 TA-aptNC 通过多价效应提供了 2 倍的增强结合能力，这进一步促进了选择性肿瘤细胞摄取能力，从而实现了增强的肿瘤成像和显著的抗肿瘤效率，而没有全身毒性。
该策略为挖掘基于内源性刺激的多价纳米器件的组装提供了有价值的见解，可用于精确诊断和高效肿瘤治疗。
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