α螺旋阳离子聚多肽是一类新型、高效的细胞穿膜和基因递送材料，在克服细胞屏障方面具有其它非病毒载体所不具备的独特优势。为提高其穿膜性能、更好地解决核酸分子不易进胞且易被内含体捕获的问题，本项目中我们向阳离子聚多肽中引入疏水芳香基团以期增强聚多肽与磷脂双分子层的相互作用，实现穿膜和基因递送的“自激活”。为进一步解决核酸分子进胞后较难释放、材料长期毒性大等基因递送过程中的另两个关键问题，我们在“自激活”聚多肽的结构基础上设计了一系列刺激响应的聚多肽。该类聚多肽在细胞内源性刺激下正电荷密度降低，α螺旋结构被破坏，最终促进核酸分子的胞内释放、消除转染后材料的长时程毒性，实现基因转染的“自调控”。在上述研究中，我们还将系统考察阳离子聚多肽的结构参数对其二级结构、穿膜机制、基因递送效率和生物相容性的影响，为其分子设计提供理论基础，最终推动这类新型高分子材料在生物医学，特别是基因治疗领域中的应用。

Cationic helical polypeptides are a new category of cell penetrating peptides and gene delivery vectors, possessing distinct advantages over traditional non-viral vectors in overcoming the various cellular barriers against gene transfer. With an attempt to strengthen the membrane activities, potentiate the gene delivery efficiencies, and reduce the toxicities, we in the current project first propose to develop helical polypeptides modified with aromatic moieties which render additional and specific interactions with the phospholipid membranes to “self-activate” the penetration as well as the transfection process. Based on such structure, we further propose to develop a set of trigger-responsive helical polypeptides that can be converted to the charge-reduced and helix-distorted state upon internal stimuli (such as reactive oxygen species (ROS) and enzyme) at the post-transfection state. As such, intracellular gene release can be promoted and material toxicity can be eliminated, collectively leading to “self-programming” of the gene delivery behavior. A systemic study will also be performed to probe the effect of polypeptide structure, such as charge density, polymerization degree, secondary conformation, topology, hydrophilicity/hydrophobicity, on the membrane penetration and gene delivery profiles, attempting to provide mechanic understandings for the molecular design. With these efforts, the proposed project will expand the utilization and application of helical polypeptides as a novel class of biomaterials, and will provide important additions to the field of gene delivery and gene therapy.