核酸-有机发光杂化材料的合成及其生物成像和传感应用

基于光学信号的传感和成像技术具有灵敏度高、特异性好、响应速度快、成本较低、能够实现非侵入性成像等特点，已成为生物医学领域中的重要工具。与无机发光材料相比，有机发光材料具有更高的光捕获能力、更高的亮度、更好的生物相容性、性能连续可调等特点。然而，当前的有机发光材料在生物成像和传感应用中仍然缺乏对生物标志物特异性的识别能力，极大限制了其临床转化和商业应用。

研究人员已经开发出了生物分子偶联策略来解决上述问题，例如寡肽偶联、酶偶联和抗体偶联。核酸分子具有独特的分子识别和组装能力、丰富的生物功能性，在纳米制造和生物医学领域受到广泛关注，尤其在基于信号动态变化的生物传感器设计和药物分子的靶向递送中显现出不可替代的地位。然而，很少有报道利用功能核酸改善有机发光材料的生物医学应用，这主要是受到合成和制备技术的限制，无法将亲水性的核酸与高度疏水的有机发光材料结合起来。因此，本论文系统性地研究了将核酸高效可控地修饰到有机发光材料上的方法，开发了一系列核酸-有机发光杂化材料，详细研究了它们的光学性质和生物学性质，拓展了它们在生物成像和生物传感中的应用。主要研究内容和结果总结如下：

克服血脑屏障的阻碍是实现近红外二区（NIR-II）纳米荧光团靶向成像脑肿瘤的重要前提。本论文开发了一种有机球形核酸，其通过疏水相互作用包覆NIR-II发光染料。这种有机球形核酸由新型的两亲性DNA嵌段共聚物——聚苯乙烯-b-DNA（PS-b-DNA）在水溶液中自组装形成的。研究发现，基于PS-b-DNA的发光杂化材料可以通过清道夫受体介导的转胞吞途径高效地跨越血脑屏障。通过表面DNA的链杂交，可以进一步修饰靶向脑肿瘤的核酸适配体，增强成像剂在脑肿瘤部位的富集。小鼠脑肿瘤荧光成像的结果显示，基于核酸杂化材料的NIR-II纳米荧光团在脑肿瘤处的荧光信号是基于传统PS-b-PEG纳米荧光团的3.8倍，显著提高的成像分辨率将有利于脑肿瘤的进一步诊断和治疗。

虽然NIR-II荧光成像实现了更深层的组织穿透，但受组织光散射和自身荧光的影响，其成像分辨率仍然亟待提高。余辉成像作为一种持续发光技术，消除了外界激发光源的影响，可实现明显高于荧光成像的信噪比。本论文通过核酸修饰技术提高了有机长余辉纳米粒子靶向肿瘤的能力，开发了一种共组装策略——将两亲性的脂质-DNA和疏水的半导体聚合物共组装成DNA功能化的半导体聚合物纳米粒子（DNA-SPNs）。进一步通过DNA-SPNs表面DNA的互补配对引入具有靶向功能的核酸适配体，赋予SPNs特异性的肿瘤靶向能力。小鼠的肿瘤余辉成像结果显示，DNA修饰的SPNs相比于未修饰的SPNs在肿瘤部位的余辉信号对比度提高了1.7倍，相关结果对实现微小肿瘤的早期诊断具有重要意义。

上述两个工作都是通过物理复合有机发光材料进而得到核酸-有机发光杂化材料，在生物应用中存在着复合结构分离从而影响生物安全性的风险。因此，论文进一步开发了将多条DNA序列共价接枝到疏水荧光共轭聚合物（FCP）骨架上的化学偶联策略，合成了两亲性的FCP-g-DNA，该方法合成产率高，产物结构明确，特别是排除了有机发光材料和DNA解离的风险。FCP-g-DNA在疏水驱动力下自组装形成球形核酸（SNA），其内核完全由FCP组成，因此最大化了其“光捕获天线放大效应”。由于FCP独特的电子离域结构和表面DNA的分子识别能力，FCP-SNA的能量传递范围可超越Förster半径，实现了传感信号的~37倍放大，可用于超低浓度的标志物检测。在传感应用中， FCP-SNA探针对microRNA的检测限低至1.7 pM，适用于单细胞水平的microRNA成像，在分子生物学、药物筛选、病理分析领域展示出很好的应用潜力。

关键词：生物传感；生物成像；有机发光材料；功能核酸；核酸-有机发光杂化材料

Sensing and imaging techniques based on optical signals have emerged as crucial tools in biological and medical research due to their superiority in high sensitivity, specificity, quick feedback, low cost, non-invasive imaging. Compared with the inorganic luminescent materials, organic luminescent materials (OLMs) exhibit higher light-harvesting capacity, higher brightness, better biocompatibility, and continuously tunable performance. However, current OLMs still lack the capability of recognizing biomarkers in bioimaging and biosensing, which greatly limits their clinical translation and commercial applications.

Biomolecule conjugation have been developed to address the above problems, such as oligopeptide conjugation, enzyme conjugation, and antibody conjugation. Nucleic acids exhibit unique molecular recognition, assembly capabilities, and rich biological functionalities, which makes them become a kind of important material in biomedical field, especially in the design of biosensors based on dynamic signal changes and targeted drug delivery. However, very few reports have utilized functional nucleic acids to improve the biomedical applications of OLMs, which is limited by technical difficulties in the combination between the hydrophilic nucleic acids with the highly hydrophobic OLMs. Therefore, in this dissertation, the methods of efficiently and controllably modifying nucleic acids onto OLMs have been systematically studied, and a series of nucleic acid-organic luminescent hybrid materials (NA-OLMs) have been developed. On the basis of the detailed investigation of their optical and biological properties, their applications in bioimaging and biosensing have been exploited. The main research contents and results are summarized as follows:

Overcoming the obstacles of blood-brain barrier (BBB) is an important prerequisite for the near-infrared second region (NIR-II) nanofluorophores in targeted imaging of brain tumors. Therefore, an organic spherical nucleic acid (SNA) is developed and it can encapsulate NIR-II fluorescent dyes through hydrophobic interactions. This organic SNA is formed by self-assembly of a novel amphiphilic DNA block copolymer, polystyrene-b-DNA (PS-b-DNA), in aqueous solution. The study found that the PS-b-DNA-based NA-OLMs could efficiently cross the BBB via the scavenger receptor-mediated transcytosis pathway. Through the strand hybridization of surface DNA, nucleic acid aptamers targeting brain tumors can be modified to further enhance the enrichment of imaging agents at brain tumor sites. The imaging of mouse brain tumors showed that the fluorescence signal of NIR-II nanofluorophore based on NA-OLMs at brain tumor was 3.8 times as high as that of the nanofluorophore based on PS-b-PEG.

Although NIR-II fluorescence imaging achieves deeper tissue penetration, its resolution still needs to be improved due to tissue light scattering and autofluorescence. As a persistent luminescence technology, afterglow imaging can achieve a signal-to-background ratio (SBR) significantly higher than that of fluorescence imaging due to the removal of external excitation light source. To confer the capability of targeting tumors on organic afterglow nanoparticles, a co-assembly strategy is developed to fabricate DNA-functionalized semiconducting polymer nanoparticles (DNA-SPNs) by the self-assembly of the amphiphilic lipid-DNA and hydrophobic SPs. Through the complementary pairing of DNA on the surface of DNA-SPNs, nucleic acid aptamers with targeting function are introduced, which endows DNA-SPNs with stronger tumor-targeting capability. The tumor afterglow imaging in mice demonstrated that DNA-modified SPNs showed 1.7-fold improvement in SBR of afterglow signal at tumor sites compared with unmodified SPNs.

In the above two works, NA-OLMs are fabricated by physically encapsulating the OLMs, and there is a risk that the composite structure will be separated and affect biological safety in biological applications. Therefore, a chemical conjugation strategy of directly grafting multiple DNA strands onto the backbone of hydrophobic fluorescent conjugated polymer (FCP) is developed to synthesize amphiphilic FCP-g-DNA. This method shows high synthesis efficiency and a well-defined product structure, especially eliminating the risk of dissociation of OLMs and DNA. The FCP-g-DNA amphiphiles self-assemble into an SNA structure under hydrophobic driving force, whose inner core is entirely composed of FCP, thus maximizing its “light-harvesting antenna amplification effect”. Due to the unique electron delocalized structure of FCP and the molecular recognition capability of the surface DNA, the energy transfer range of FCP-SNA can exceed the Förster radius, achieving ~37-fold amplification of the sensing signal, which can be applied in marker detection at ultra-low concentrations. Therefore, it was observed that the detection limit of this FCP-SNA probe for microRNA detection reached as low as 1.7 pM in a sensing applications. Further, the FCP-based SNA probe was applied for microRNA imaging at the single-cell level.

Keywords: biosensing, bioimaging, organic luminescent material, functional nucleic acid, nucleic acid-organic luminescent hybrid material

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