A material toolbox for engineering targeted lipid nanoparticles for RNA therapies

RNA therapeutics are rapidly redefining the landscape of modern medicine, offering programmable solutions to target diseases at the genetic level. Their success, exemplified by FDA-approved siRNA drugs and mRNA vaccines in clinical use, is primarily enabled by lipid nanoparticles (LNPs), which protect RNA, facilitate its intracellular delivery, and enhance endosomal escape. However, LNPs exhibit limited organ selectivity, often accumulating in the liver, which restricts broader clinical translation. This review presents a materials-centered framework for engineering targeted LNPs that improve therapeutic efficacy in target organs while minimizing off-target effects. We first examine surface functionalization strategies using active targeting ligands such as antibodies, peptides, aptamers, carbohydrates, and small molecules. We then highlight approaches to modulate organ tropism through intrinsic lipid component design, such as rational design of ionizable lipids, use of lipid additives, and tuning of lipid composition. Key analytical methods for evaluating targeting efficiency, including in vitro and in vivo assays, are also discussed. Finally, we examine emerging applications of targeted LNPs across diverse disease areas, including cancer, women’s health disorders and neurological diseases, with an outline on future directions. Overall, this review aims to guide the rational design of next-generation targeted LNPs by presenting a toolbox of material strategies to facilitate the safe and effective application of RNA therapeutics.