大分子自组装：生物分子识别作用的引入和模拟糖萼的构建及其生物学功能 (领域：一、二)

Based on the “non-covalently connected micelle”(NCCM) strategy developed by the applicant, this project aims at the target of constructing macromolecular self-assemblies towards biological functionalities. The core of the research contents includes 1) Dual molecular recognitions in self-assembly. Carbohydrate-protein interaction as a typical “biological molecular recognition” is introduced into self-assembly of synthetic polymers. It would work together with the host-guest interaction of “chemical molecular recognitions” to achieve various new types of self-assembled structures at different levels. Much attention would be paid on the orthogonality and complementation of the two kinds of molecular recognitions as well as the mechanism of the self-assembly; 2) Construction of polymeric vesicles mimicking glycocalyx (PV-Gx) via NCCM strategy: By design and synthesis of polymers containing glycosides with different architecture, molecular weight and density of glycosides, as well as the optimization of self-assembly conditions, the composition and morphology of the PV-Gx can be controlled to meet various requirements of the subsequent biological studies. i.e. molecular recognition behavior of lectins from plants and animals to the glycosides on the surface of PV-Gx. Furthermore, PV-Gx composed of the glycosidic chains characteristic of tumor cells (tumor-associated carbohydrate antigens) is constructed for studying the biological functions and molecular mechanism of the sugar chains. All the researches based on PV-Gx are expected to provide new views and ideas for the development of glycobiology.

本项目是以申请人在大分子自组装方面的独创的‘非共价键合胶束’(NCCM) 研究路线和成果为基础，瞄准构建以生物学功能导向的大分子自组装体系为目标提出的。其核心研究内容为：1.将糖－蛋白质识别作用为代表的“生物分子识别”引入大分子自组装体系，使其和主－客体的“化学分子识别”作为共同驱动力，构筑多层次、多组分的组装体。深入研究和利用多重相互作用的正交性和互补性，探求复杂组装体系的自组装规律。2.通过NCCM策略构筑模拟细胞表面糖萼的大分子自组装囊泡，通过各种含糖聚合物的设计和合成以及自组装条件的优化，实现模拟糖萼的结构和组成的有效控制，以满足后续生物学功能研究的要求。研究动/植物凝集素对模拟糖萼囊泡表面糖链的识别行为，构建具有癌细胞表面特征性糖链的模拟糖萼囊泡，研究该糖链的生物学功能和分子机制。基于模拟糖萼囊泡的研究将为糖生物学的发展提供新的视角和思路。

按照研究计划，本项目的研究内容包括两个部分，一是向自组装体系中引入糖-蛋白质的分子识别作用，探讨复杂自组装体系的构建；二是构筑含糖组装体模拟细胞表面糖萼并研究其生物学功能。在过去4年中，我们按照计划开展研究工作，成功构建了同时含有超分子化学分子识别作用和糖-蛋白质相互作用的大分子自组装体，并探讨了含糖组装体的生物学功能。本项目所取得的成果有：(1) 提出并发展了一个新的基于糖-蛋白相互作用和p−p相互作用协同诱导蛋白质分子精确组装的新策略，成功构筑了蛋白质晶体组装体和粒径均一的微米管。(2) 研究了由糖参与的化学反应控制的含糖聚合物的自组装，发展了一个具有普遍意义的自组装新途径并发现了一个胶束原位翻转过程。(3) 选择了糖的免疫学功能作为组装体功能研究的突破点，发现含糖组装体可用于调节肿瘤免疫微环境，在肿瘤免疫治疗方面有潜在的应用前景。这三部分内容都超出了原计划书的预期，成为新的研究生长点。四年来共发表文章30篇，包括 1篇Nature Communications，3篇J. Am. Chem. Soc.，1 篇Adv. Mater.，2篇Small，5篇ACS Macro Letters， 1篇Macromolecules，1篇Biomacromolcules 等。ACS Macro Letters文章被选为ACS editors' Choice在ACS网站上滚动highlight；J. Am. Chem. Soc.文章被选为2016年9月当期封面。