新型蛋白运输载体材料的制备及其应用研究

Proteins play a crucial role in life, taking part in all vital processes in the body. Compared with small-molecule drugs, gene and protein therapeutics possess several advantages attributed to their highly specific and superior biocompatibility. However, current gene therapy often suffers from its instability, immunogenicity and limited transfection efficiency. From a therapeutic perspective, protein therapeutics is therefore a safer alternative compared with gene therapy because no random or permanent genetic changes are involved. Although the last few decades have witnessed significant progresses in the development of protein therapeutics, several challenges still remain to be addressed, such as stability, burst release, targeting, etc. Therefore, the goal of this project is to design novel protein delivery systems for enhancing their stability, achieving "on demand” precise release and enhancing therapeutic efficacy. In our design, hydrophobic and partial electrostatic interaction was used to facilitate the encapsulation of proteins into the structure of the vector, copper free click induced crosslinking avoids protein leaking and inactivating, the introduction of stimuli-responsive group is capable of inducing disassembly of the system in response to environmental stimuli, and targeting delivery can guarantee the release of proteins at a targeting site. More importantly, three kinds of work will be done to prove the biocompatibility and effectiveness of the designed functional protein delivery systems in the treatment of diseases. We hope the completion of this proposal will generate efficient protein carrier systems and be helpful for promoting the clinical application of protein therapy.

蛋白质在生命中起着至关重要的作用，参与身体的所有重要过程。蛋白质治疗相对于药物和基因治疗具有更好的专一性、安全性和更广泛的适应性，在疾病治疗方面显示了广阔的应用前景，但目前存在的关键问题是如何寻求有效的载体将功能蛋白高效、专一的运输到肿瘤组织和细胞中。因此，本项目拟利用所设计的载体材料与蛋白之间的部分静电和疏水相互作用，通过在水溶液中室温条件下简单的混合交联，将目的蛋白有效地包载起来，同时利用靶向运输以及疾病微环境响应性解组装诱导蛋白释放的特点，探索功能蛋白进行疾病治疗的有效性。此外，我们将进一步制备药物自组装体进行多蛋白联合用药，使整个体系在响应性释放药物和抑癌蛋白的同时消耗营养物质，增强治疗效果，以期为推动蛋白质治疗技术及其向临床应用转化提供新的思路和策略。

蛋白质疗法作为一种新兴的治疗手段在疾病治疗方面显示了广阔的应用前景。但目前存在的关键问题是如何寻求有效的载体将功能蛋白高效、专一的运输到肿瘤组织和细胞中。本项目设计合成了具有在疾病微环境下响应性断裂以及高靶向性的新型蛋白运输载体并成功将功能蛋白递送到细胞内，实现了相关疾病的治疗。该载体利用疏水和部分静电相互作用将目的蛋白有效地包埋于疾病微环境敏感的交联结构中，从而有效地保护目的蛋白免受血清酶降解或非特异性吸附造成的失活。此外，该载体与蛋白进行包载的过程非常温和，不需任何修饰和溶剂置换步骤，避免了负载过程中造成蛋白的失活，为利用蛋白质技术进行疾病治疗提供了新思路。在此基础上，本项目还构建了细胞核靶向的多功能自组装体，实现了多组分蛋白和药物细胞核内运输，为在细胞核水平上进行功能调控提供了新的模式和策略。