It is crucial to deliver anticancer drugs to target cells with high precision and efficiency in clinical medicine. While novel nanomaterials have been shown to enhance the delivery efficiency once they reach the target, it remains challenging for precise drug delivery to overcome the non-specific adsorption and off-target effect. To meet this challenge, we report herein design of a novel DNA nanostructure to act as a DNA nanoscale precision guided missile (D-PGM) for highly efficient loading and precise delivery of chemotherapeutic agents to specific target cells. The D-PGM consists of two functional parts: warhead (WH) and guidance/control (GC). The WH is a rod-like DNA nanostructure as an anticancer drug carrier, whose trunk is a three-dimensionally self-assembled DNA nanoscale architecture from the pro-grammed hybridization among two palindromic DNA sequences in the x-y dimension and two common DNA oligonucleotides in the z-direction, making the WH to possess a high payload capacity of anticancer drugs. The GC is an aptamer-based logic gates assembled in a highly organized fashion capable of performing cell-subtype-specific recognition via the sequential disassembly, mediated by cell-anchored aptamers. Because of the cooperative effects between the two essential structures, the GC logic gates operate like the guidance and control system in precision-guided missile to steer the doxorubicin (DOX)-loaded DNA WH toward target cancer cells, leading to the selective and enhanced therapeutic efficacy. Moreover, fluorophores attached to geometrically different locations of D-PGM and DOX fluorescence dequenching upon release enable the intracellular tracing of DNA nanostructures and drugs. The experimental results demonstrate that, by mimicking the functionalities of military precision-guided missile to design the sequential disassembly of GC system in multi-stimuli-responsive fashion, our intrinsically biocompatible and degradable D-PGM can accurately identify target cancer cells in complex biological milieu and achieve active targeted transport of conventional chemotherapeutic drugs. The success of this strategy indicates the precise delivery of anticancer drugs to specific target cells by designing smart DNA drug-delivery nanocarrier platform, thus paving the way for specific cell identity and targeted cancer therapy.

中文翻译：

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包含弹头和制导控制的精确制导导弹样 DNA 纳米结构，用于体外和体内将基于适体的靶向药物递送到癌细胞中

在临床医学中，将抗癌药物以高精度和高效率输送到靶细胞至关重要。虽然新的纳米材料已被证明可以在到达目标后提高递送效率，但精确的药物递送克服非特异性吸附和脱靶效应仍然具有挑战性。为了应对这一挑战，我们在此报告了一种新型 DNA 纳米结构的设计，用作 DNA 纳米级精确制导导弹 (D-PGM)，用于高效装载和精确递送化学治疗剂到特定靶细胞。D-PGM 由两个功能部分组成：弹头（WH）和制导/控制（GC）。WH是一种棒状DNA纳米结构作为抗癌药物载体，其主干是一个三维自组装的 DNA 纳米级结构，由 xy 维度的两个回文 DNA 序列和 z 方向的两个常见 DNA 寡核苷酸之间的程序化杂交，使 WH 具有高抗癌负载能力药物。GC 是一种基于适体的逻辑门，以高度有组织的方式组装，能够通过细胞锚定适体介导的顺序分解进行细胞亚型特异性识别。由于这两种基本结构之间的协同作用，GC 逻辑门就像精确制导导弹中的制导和控制系统一样，将载有阿霉素 (DOX) 的 DNA WH 导向靶标癌细胞，从而实现选择性和增强的治疗功效。而且，附着在 D-PGM 几何不同位置的荧光团和 DOX 荧光在释放时去猝灭，能够在细胞内追踪 DNA 纳米结构和药物。实验结果表明，通过模仿军用精确制导导弹的功能，以多刺激响应的方式设计GC系统的顺序拆卸，我们具有内在生物相容性和可降解性的D-PGM可以准确识别复杂生物环境中的靶癌细胞。并实现常规化疗药物的主动靶向转运。该策略的成功表明，通过设计智能DNA药物递送纳米载体平台，可以将抗癌药物精确递送至特定靶细胞，从而为特定细胞识别和靶向癌症治疗铺平道路。