多功能超病毒递送系统的构建及其作用机制的研究

Currently, bioinspired strategy emerges as a powerful and challenging approach for developing advanced materials. Here we combine ‘viral inspirations’ and ‘intellegent design’ to creat multifunctional artificial viruses (MAVs) for synergetic tumor therapy, which are expected to provide both virus-mimicking properties and artificial intelligence. With a rational design, multifunctional amphiphilic dendrimers can self-assemble into viral capsid-mimicking assemblies for hierarchically packaging drug, gene and nanoparticles. On the other hand, tumor membrane with synthetic fusion peptide could be engineered as artificial envelopes. Then, MAVs will be constructed after cooperative assembly of artificial capsid and envelope, with the following advantages: (i) stealthy surface to resist protein interactions and prolong blood circulation time, (ii) well-defined nanostructure for passive targeting to solid tumor site, (iii) receptor-mediated targeting and membrane fusion to enhance tumor-specific cellular uptake, (iv) virus-mimicking intercellular transport and subcellular targeting, (v) biological-dependent controlled delivery of drug, gene and Au nanoparticles. And the synergetic antitumor effects of MAVs in vitro and in vivo will be studied in detailed; furthermore, we will track MAVs in vitro and in vivo to disclose the the delivery mechanism. We hope that this work will set the stage for the development of multifunctional artificial viruses as well as efficient tumor therapy.

近年来，生物启发型的构建策略成为了发展多功能先进材料的重要方向。本项目结合“病毒的生物启发”和“针对肿瘤特征的智能设计”，通过多功能材料设计与合成、多元协同自组装技术，构建具有仿病毒结构和功能、高效靶向性、生物感知性及多客体分子共载等特征的超病毒递送系统，在肿瘤治疗中实现对多种生物活性分子安全高效的递送和协同治疗作用，并探索超病毒递送系统的作用机理。拟通过合成多功能两亲性肽类树状大分子，利用自组装技术分层次负载药物、基因和光热无机纳米粒子以实现多策略联合治疗，构建具有生物感知性的衣壳；整合肿瘤细胞膜的功能成分和合成的融合肽制备多功能囊膜；诱导人工囊膜包裹衣壳结构装配形成超病毒递送系统。考察超病毒递送系统的协同抗肿瘤效果及其在细胞和动物水平的递送机制。本研究希望为构建高级生物启发型递送系统提供新策略，为肿瘤治疗发展新一代的多功能超病毒递送系统，也为设计新型生物启发型递送系统积累依据和基础。

生物启发型的构建策略是发展先进纳米载体的重要方向，本项目聚焦于病毒结构与功能仿生，成功整合了肿瘤特异性的智能设计，开展了一系列超病毒载体系统的研究，完成了各项研究目标，解决了相关的关键科学问题。基于仿生树状高分子及超分子构筑，仿造了病毒程序化克服多重屏障、侵染靶组织的功能，创造了类病毒载体的组织与细胞双重高效渗透功能，突破性地实现了仿病毒生物活性的肿瘤双向“适应与调控”功能。我们不仅创制了多例能够安全高效递送协同递送多种生物活性分子的超病毒递送系统，而且揭示了其仿生递送机制及协同抗肿瘤效果；本项目的研究成果对构建全新一代的仿生载体材料具有指导意义。本项目资助的系列研究成果发表在Advanced Materials、ACS Nano、Materials Horizons、Chemistry of Materials、Theranostics等国际重要期刊共9篇（均标注本项目资助号），申请及授权国家发明专利共8件。