Recent Advances in mRNA-LNP Delivery Systems for Extrahepatic Organs: A Review
Ying Bai, Li Cui, Tianshu Liu, Zhen Wang, Haiyan Cao, Shukun He, Jiani Qiu, Yingxin Li, Yilan Zhou, Jiawei Shi, Jing Wang
Abstract
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.