聚合物-多酚纳米载体的设计、组装及其与生物界面的相互作用研究

The development in nanotechnology has enabled the design of colloidal particles with diverse physicochemical properties and biological functionalities, which are exploited as intelligent nanocarriers for diagnostic and therapeutic applications in biomedical realm. When entering biological environments, well-established nanocarriers exhibit unexpected properties and dynamics, owing to their interaction with the biological interfaces. As soon as entering the biological environment, nanocarriers adsorb a protein predominating biological surface coating, known as the “protein corona”. The protein corona plays important roles in determining the fate of nanocarriers in biological systems by providing nanocarriers with unique biological identities. Therefore, to optimize the design of a certain nanocarrier, it is essential to get the whole picture of the interactions between the nanocarrier and the diverse biological interfaces. Herein, we engineer a series of polymer-phenol nanocarriers based on the assembling mechanism of the metal-phenolic network (MPN), and investigate the interaction between nanocarriers and biological interfaces, including the formation of protein coronas in a series of biological environments with diverse complexities, the changes of nanocarrier properties upon the formation of protein coronas, the recognition and uptake of corona-coated nanocarriers by various cells/tissues, as well as the subsequent physiological responses upon the uptake of nanocarriers. We aim to take the influence of biological interfaces into consideration at the early stage of nanocarrier-designing. Particularly, the formation of protein coronas or the adsorption of certain biomolecules on the surface of nanocarriers can provide new opportunities for engineering nanocarriers to achieve specific physiological objectives, including enhanced circulation and targeting abilities, as well as reduced toxicity and harmful side-effects of nanocarriers.

随着纳米技术的发展，具有不同物生物学功能的胶体粒子的组装得以实现，并被作为纳米载体应用于一系列疾病的诊断与治疗研究中。当纳米载体进入生物环境中时，会即刻在其表面吸附一层以蛋白质为主的生物表层，称为“蛋白冠”。蛋白冠会赋予纳米载体特定的生物特性，并对纳米载体在生物系统中的命运起到决定性作用。本项目利用金属-多酚网络结构的形成机制，设计并制备不同的聚合物-多酚纳米载体，系统深入地研究纳米载体与生物界面之间的相互作用，包括在不同复杂程度的生物环境中蛋白冠的形成，蛋白冠形成后纳米载体的特性变化，不同生物细胞／组织对蛋白冠包被的纳米载体的识别与摄取，以及摄取纳米载体后引发的一系列生理反应等。本项目旨在将生物界面对纳米载体性能的影响纳入载体设计的早期阶段，特别是特定组分的蛋白冠的形成可以为载体的设计和优化提供新思路，从而提高载体的循环时间和生物靶向性，同时降低纳米载体的毒副作用。

多酚化合物广泛存在于自然界所有植物以及大多数动物和微生物体内，以其优良的生物相容性、生物亲和力和理化活性在生物医用材料的设计、开发和优化中扮演着越来越重要的角色。本项目利用天然植物多酚化合物为基础原料，基于多酚化学原理，开发了一系列聚合物-多酚纳米材料，并对其在疾病的诊断和治疗等方面的应用进行探索。基于多酚化合物对不同材料的亲和能力，本项目设计合成了多种多酚基纳米胶囊，对其与生物系统的相互作用进行调控，并利用纳米胶囊装载生物酶，实现细胞内的可控释放和级联效应。使用多酚化合物含量丰富的天然植物原料可以简便地实现多酚基纳米颗粒的合成并将其用于肿瘤的联合治疗。此外，基于多酚化合物与生物大分子优良的亲和力，实现多酚基双网络自愈合水凝胶的开发，并将其用作优良的止血剂。本项目基于天然植物多酚优良的物理、化学和生物活性，探索其在生物医用材料的开发中的作用，不仅开发出一系列简单易得、成本低廉的新型疾病诊疗材料，更为多酚化学和多酚基材料的进一步发展和完善提供实验支撑。本项目研究期间发表论文6篇，申请国家发明专利1项；协助导师培养研究生4名，其中2名取得博士学位，1名取得硕士学位，1名博士研究生在读；项目直接经费预算27.0000万元，支出25.8637万元，结余1.1363万元，计划用于本项目研究的后续支出。