基于核酸功能化的AIE-噬菌体缀合物的吞噬小体内细菌的灵敏检测和定向杀伤

胞内菌引发的慢性感染疾病严重威胁着人类的健康，发展特异、灵敏的在体检测和清除方法对胞内菌感染疾病的早期诊疗具有重要意义。目前如何将诊疗剂稳定地递送至包裹细菌的细胞内甚至是亚细胞器内，以及实现细菌的靶向识别是亟待解决的关键问题。本项目拟将已有的AIE（聚集诱导发光材料）−噬菌体与带适配体的球形核酸相整合，构建双靶向的AIE−噬菌体球形核酸系统（SNAPs）。利用适配体对巨噬细胞靶向识别，实现SNAPs的选择性内化，同时利用球形核酸与细菌进胞路径一致的特点，实现SNAPs在亚细胞器吞噬小体内的有效定位。进而开展噬菌体靶向的细菌识别，促进AIE在病原菌表面聚集，增强细菌表面近红外荧光强度和光动力活性，在有效降低巨噬细胞毒性的同时建立在体胞内菌灵敏检测和定向杀伤新方法。本项目为构建新型胞内菌感染诊疗探针提供新思路，为临床胞内菌引发的慢性感染疾病的精准诊疗提供新策略。

Chronic infection diseases caused by intracellular bacteria have seriously threatened the health of human being. There is an urgent clinical need to diagnose pathogen in vivo with high specificity and sensitivity and effectively eliminate them at an early stage for intracellular bacterial infection therapy. Currently, how to stably delivery the theranostic probe into desired subcellular sites entrapping bacteria and achieve targeted recognition are key problems that need to be solved urgently. In our project, we will construct dual-targeted spherical nucleic acid−AIE−Phage bioconjugates by integrating the existing AIE−Phage with aptamer-linked spherical nucleic acid conjugates. The aptamer-linked spherical nucleic acid conjugates that specifically recognize macrophage will accelerate the internalization of SNAPs. Because of the same internalization path between SNAPs with bacteria, SNAPs can efficiently localize inside the phagosome. The targeting ability inherited from the bacteriophage enables SNAPs to specifically recognize the host bacteria with preserved infection activity of phage itself, and retain enhanced AIE accumulation on the surface of phagosome-entrapped bacteria inside the macrophage which will enhance NIR fluorescence intensity and photodynamic inactivation activity. Therefore, maximum therapeutic efficacy and minimum cytotoxicity toward macrophages were achieved. This project will offer a new perspective to the construction of a novel theranostic probe for intracellular bacterial infection, and contribute to the development of the pinpoint theranostic technique for intractable chronic infection caused by intracellular bacteria.