Engineering Lipid Nanoparticles for Precision RNA Delivery: Design Principles, Targeting Strategies, and Clinical Prospects

ABSTRACT Lipid nanoparticles (LNPs) represent the most clinically advanced platform for RNA delivery and have enabled major breakthroughs in vaccines and gene therapies. However, their broader application is still limited by inefficient extrahepatic delivery, immunogenicity, and insufficient control over tissue‐ and cell‐specific targeting. This review provides a mechanistic overview of recent advances in LNP engineering for RNA therapeutics. We systematically analyze how key physicochemical parameters and structural elements, including ionizable lipid headgroups, linkers, tail architectures, helper lipids, cholesterol analogs, and surface modifications, govern biodistribution, endosomal escape, immunogenicity, and therapeutic efficacy. Emerging targeting paradigms, encompassing ligand‐mediated active targeting, formulation‐driven intrinsic targeting, and administration‐route optimization, are discussed with a focus on tumor and immune organ delivery. In addition, we highlight enabling methodologies such as DNA barcoding, multiplexed in vivo screening, and data‐driven lipid design that are reshaping LNP discovery. Finally, translational challenges and future directions for precision RNA delivery in cancer therapy are discussed, with an emphasis on how rational LNP design can be leveraged to overcome cancer‐specific barriers such as tumor heterogeneity, stromal constraints, and the immunosuppressive tumor microenvironment (TME).