双光子控制下的DNA纳米结构的构型改变及其潜在的可控递送应用上的研究

DNA not only is a biopolymer, but also it is emerging as a powerful and versatile nanoscale building block for the construction of precisely self-assembled nanostructures by virtue of its desirable molecular recognition property, precise nucleobase sequence control and ease of chemical functionalization. Disassembly/reconfiguration of self-assembled DNA nanostructures has drawn interesting attention because of their potential applications in biology and nanoscience. In this project, we demonstrated the first example of two-photon-regulated, shape-changing DNA nanostructures. Specifically, we designed a new photon-responsive DNA nanotube, by integrating a well-defined DNA nanotube, with a two-photon cleavable module that enables the opening of the cavities of tube and becomes partially single-stranded in response to two-photon excitation condition with near infrared laser. This would induce the conformational change of nanotubes from linear to bending features. Subsequently, this clean and safe strategy for reconfiguration of DNA nanotube would facilitate the remote control of the release of encapsulated cargos in both spatial and temporal manner, without destroying the well-organized biological systems. From both scientific and technological points of view, finding of this proposed research is of great importance to provide a strong basis of developing two photon-responsive DNA nanostructures and offers an innovated, safe and clean strategy for the active control of their conformational changes. Consequently, this two-photon induced structural change would greatly contribute to biomedical applications, particularly in remote control of cargo release from programmable DNA nanocarriers for drug delivery. We foresee DNA nanotechnology can bring us one step closer to the realization of nanomaterials that can be perform complicated tasks inside our body with high specificity and high precision.

DNA不仅是遗传物质的载体，更由于其理想的分子识别和简易的化学修饰，近年来作为一个强大的多功能的纳米结构单元浮现于构筑精密的自组装纳米结构的领域。而DNA纳米结构的重构也正在吸引大家的研究兴趣因为该过程在生物及纳米科学上有着诱人的潜在应用。在本研究计划中，我们展示了首例双光子调控下形状可变的DNA纳米结构，通过将双光子可切的组件整合到结构良好的DNA纳米管中，实现在近红外的双光子激发下纳米管从直线型变为弯曲型并打开空腔。因此，这种洁净安全的重构DNA纳米管的策略可在不干扰生物体系的情况下帮助实现在时间上和空间上对DNA纳米管所包覆的负载物的双重远程控制式释放。从科技的角度来说，我们的研究的重要意义在于设计的DNA纳米结构在双光子诱导的结构改变将会为生物医学应用如药物递送带来可观的贡献，同时在实现纳米材料在人体内以高度的特异性和精密性来完成复杂的任务，DNA纳米技术使我们又前进了一大步。

由于易于合成及修饰、可编译性强，DNA作为纳米构建领域的新兴材料，近年来逐渐成为纳米研究领域的热点。由于光具有低损伤性、不接触性等优势，开发双光子响应的三维DNA纳米结构、通过双光子刺激实现DNA纳米结构的构型控制，在纳米技术和纳米医药领域具有重要的意义。本项目中，我们旨在设计并组装具有双光子响应性的三维DNA纳米结构，并探究其潜在可控递送应用。我们成功组装了具有双光子响应性的DNA纳米管，实现了双光子辐射对DNA纳米管形态的主动控制。DNA纳米管在未经双光子照射处理的情况下为直的刚性纳米管，在800纳米飞秒激光照射之后，DNA纳米管的形态发生了显著的变化，呈现出弯曲的柔性特征。DNA纳米管的刚性长度也从25.9±1.4纳米变成8.9±1.7纳米。按照同样的构建策略，我们成功组装了能够对于不同波长的光响应的DNA纳米逻辑门，以单光子或双光子为信号输出实现了可逆的“或（OR）”逻辑操作。我们在研究过程中发现， DNA纳米管对负载物的包覆效率很低，且对负载物有明确的尺寸要求，我们目前无法找到一种普适性的方法实现对负载物的高效包覆。因此我们选择用共价连接方式将负载物连接到DNA链段上，并在此基础上实现了负载物沿DNA纳米管的可逆光控分布。构建了新型DNA纳米笼和四面体。我们系统研究了DNA纳米结构的生物稳定性和细胞毒性，发现其具有较强的酶解抗性、生物相容性较高。我们还构建了新型的双亲性DNA纳米笼，并实现了小分子抗癌药物对MCF-７癌细胞的有效递送，该体系可以导致显著的癌细胞凋亡。另外，我们提出了新型三维DNA四面体的构建策略， 在室温下以定量产率得到了单分散且热力学稳定的非常规梯形排列的DNA四面体。本项目中，我们发表核心论文2篇，综述论文２篇，培养博士生２名，在读博士生3名和研究助理1名。我们的研究结果证明，双光子响应性DNA纳米结构在纳米技术、纳米医学等领域都具有潜在应用。

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