Novel Lipid Nanoparticle (LNP) Delivery Systems Enabling the Advancement of RNA Therapeutics

ABSTRACT 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.