Bai Ying, Cui Li, Liu Tianshu, Wang Zhen, Cao Haiyan, He Shukun, Qiu Jiani, Li Yingxin, Zhou Yilan, Shi Jiawei, Wang Jing
Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Clinical Research Center for Medical Imaging in Hubei Province, Wuhan 430022, China.
Mol Pharm. 2025 Aug 4;22(8):4474-4493. doi: 10.1021/acs.molpharmaceut.5c00385. Epub 2025 Jul 11.
Lipid nanoparticles (LNPs) as gene delivery vectors have revolutionized the therapeutic paradigm in mRNA therapy. The pH-dependent lipid components can prevent endosomal retention of mRNA and promote the cytoplasmic translation of therapeutic proteins. However, current technologies still face two core challenges: the nonspecific liver accumulation rate of 30-90% after systemic administration, which is an organ targeting issue, and the inefficient cytoplasmic delivery with only 1-4% of nucleic acids escaping from endosomes. These problems severely limit their application in the treatment of extrahepatic diseases. This review systematically elaborates on the molecular composition and structure-function relationship of LNPs and explores the causes of their extrahepatic delivery obstacles. At the same time, we propose innovative strategies to enhance organ selectivity and endosomal escape efficiency. Additionally, through existing preclinical studies, key bottlenecks such as immune response control and quality control in large-scale production for the clinical translation of current technologies are revealed, providing a multidisciplinary theoretical framework for the development of the next generation of intelligent LNPs.
脂质纳米颗粒（LNPs）作为基因递送载体，彻底改变了mRNA治疗的治疗模式。pH依赖性脂质成分可防止mRNA在内体中滞留，并促进治疗性蛋白质的细胞质翻译。然而，当前技术仍面临两个核心挑战：全身给药后30-90%的非特异性肝脏蓄积率，这是一个器官靶向问题；以及低效的细胞质递送，只有1-4%的核酸能从内体中逃逸。这些问题严重限制了它们在肝外疾病治疗中的应用。本综述系统阐述了LNPs的分子组成和结构-功能关系，并探讨了其肝外递送障碍的原因。同时，我们提出了增强器官选择性和内体逃逸效率的创新策略。此外，通过现有的临床前研究，揭示了当前技术临床转化中免疫反应控制和大规模生产质量控制等关键瓶颈，为下一代智能LNPs的开发提供了多学科理论框架。
