脂质体递送系统的结构设计、生物界面与动态状态转移

Structural Design, Biointerfaces and Dynamic State Transitions in Liposomal Delivery Systems

摘要: 脂质体兼具亲水性水相内腔和疏水性脂质双层，因此能够承载不同理化性质的药物，并可通过脂质组成、膜结构和表面修饰调节其体内行为。传统研究常以粒径、粒径分布、ζ电位、包封率和配体密度等指标描述脂质体，但这些指标主要反映制剂在某一时间点的物理状态。近年来的直接研究表明，脂质体从制备、灭菌和储存到接触血浆、细胞摄取及重复给药，其膜结构、表面吸附组分和载荷状态均可能发生变化。本文采用叙述性综述方法，以可核验的脂质体原始研究为主要依据，从装载与膜结构、生物界面、仿生膜工程、重复给药以及制造与质量控制等方面重新梳理脂质体递送系统。重点讨论药物–环糊精–脂质体体系、芳香化脂质体、多层多囊脂质体、蛋白冠、巨噬细胞膜包覆和细胞外囊泡–脂质体融合等研究，并结合PEG化脂质体重复给药产生的加速血液清除现象，提出“状态转移–功能保持”的分析思路。该思路并非已有公认理论，而是对现有证据的组织方式：一种结构设计的意义不能仅依据初始粒径或包封率判断，而应进一步考察其在制造、血液环境、细胞内过程和重复暴露后的功能是否仍然存在。未来研究需要加强同批次纵向表征、人源生物流体评价、重复给药免疫学研究，以及工艺参数、关键质量属性和生物效价之间的关联，从而提高脂质体研究的可重复性和转化解释力。

Abstract: Liposomes can accommodate hydrophilic and hydrophobic drugs within an aqueous core and lipid bilayer, respectively, while their membrane composition and surface chemistry can be engineered to alter drug retention and biological interactions. Conventional characterization often emphasizes particle size, polydispersity, zeta potential, encapsulation efficiency and ligand density, but these measurements represent a formulation at a defined time point. Experimental studies show that liposomes may undergo structural and interfacial changes during manufacturing, sterilization, storage, exposure to biological fluids, cellular uptake and repeated administration. This narrative review reorganizes evidence from verifiable liposome studies on drug-in-cyclodextrin-in-liposome systems, membrane chemistry, multilamellar-multivesicular structures, protein corona, biomimetic membrane coating, extracellular-vesicle/liposome fusion, PEGylation and manufacturing. A state-transition-function-retention perspective is proposed as an organizing framework rather than an established theory. The central implication is that formulation attributes measured at the initial state should not be treated as stable surrogates for in vivo performance. Instead, the intended function of a liposome should be evaluated across relevant transitions from formulation to manufacturing/storage, biofluid exposure, intracellular processing and repeated dosing. Future work should integrate longitudinal characterization of the same batch, human biofluid variability, repeat-dose immunology and process-quality attribute-bioactivity relationships, in order to enhance the reproducibility and translational interpretability of liposome research.