Honglei Zhang, Shaowei Han, Xueyan Zhang, Jingxuan Ma, Lijie Jin, Yanfeng Wang, Yuqing Ma, Teng Ma, Fei Yu, G. Song
Lipid nanoparticle (LNP)-mRNA technology has profoundly transformed the biomedical landscape, establishing itself as a highly versatile and powerful platform with substantial therapeutic and prophylactic potential across a wide range of diseases. This review summarizes recent advances in LNP delivery systems aimed at unlocking the full potential of RNA therapeutics. Key focuses include: 1) the design and screening of novel lipid molecules to improve mRNA delivery efficiency and targeting; 2) optimization of administration routes, LNP surface functionalization, and formulation components; and 3) advances in lyophilized LNP formulations. We also highlight the growing integration of artificial intelligence (AI) for designing next-generation LNPs and overcoming existing translational barriers. Furthermore, the review provides a comprehensive overview of clinical applications of RNA-LNPs in infectious diseases, cancer immunotherapy, gene therapy, cell-based therapeutics, and RNAi-LNP therapeutics, offering systematic strategies to enhance delivery efficacy and translational capacity. Finally, we discuss the future directions and unresolved challenges, including multimodal fusion delivery methodology of LNP and non-LNP carriers, the interdisciplinary integration of various fields, and the bottleneck of extrahepatic delivery strategies, offering systematic insights into the translational pathway of mRNA-LNP therapeutics.