生物技术的迅速发展使生物大分子药物成为当今药物研发中最具临床应用前景的领域。然而，生物大分子药物存在体内易降解、半衰期短、靶向选择性低、难穿透细胞膜、口服生物利用度低，易引起过敏反应等问题。采用高效递释系统为解决上述难题提供了可能，合理构建生物大分子药物高效递释系统（BDDS）并阐明其构建机理是首要内容。本课题拟从药物、载体、机体三者间的相互作用关系入手，合理设计并构建多肽蛋白、抗体、核酸和疫苗的高效递释系统。从结构出发，采用生物正交化学方法建立PEG定点修饰的蛋白和抗体药物BDDS；从改善药动学性质出发，以物理包载、电荷作用和疏水组装原理为基础结合功能性载体材料构建缓释、靶向纳米BDDS；从提高患者用药顺应性出发，构建相转变、温敏及环境响应型长效缓释凝胶BDDS。探索BDDS载体构建机理优化载体设计，为BDDS的研发和临床转化奠定基础。

With the rapid advancement in biotechnology and bioengineering, biomacromolecular therapeutics has become the most promising field in drug discovery and development. However, very few biomacromolecules have reached the clinical stage due to their poor stability, limited permeability across cell membranes, short half-life, and low selectivity, which often result in poor oral bioavailability and immunogenic host responses. Biomacromolecular drug delivery system (BDDS) thus provides a possible solution to above issues. Rational design of BDDS and elucidation of the engineering principles remain the top priority in this project. Regarding the interrelationships between drugs, carriers, and human body, this proposal aims to develop efficient BDDS for proteins/peptides, antibodies, nucleic acids, and vaccines. Specifically, to stabilize structure and improve stability, BDDS for peptides/proteins will be established using PEGylated peptides/proteins or antibodies via “bioorthogonal chemistry”; to improve pharmacokinetic profiles, multifunctional nanoscale BDDS with improved targetability and controlled release profiles will be developed based on physical encapsulation/entrapment, charge interaction, and hydrophobic self-assembly; to improve patient adherence, depot BDDS with sustained release and long-term effect will be developed including phase-separation, thermosensitive and environment-sensitive hydrogels. Together, we aim to explore the principles of BDDS engineering design and to optimize the formulation and construction of BDDS, which may significantly contribute to the translation and clinical application of biomacromolecular therapeutics.