Emerging Lipid Nanoparticle Targeting Strategies for Extrahepatic Delivery of RNA Therapeutics

ABSTRACT Lipid nanoparticles (LNPs) have transformed RNA therapeutics through their high delivery efficiency, scalable manufacturing, and favorable safety profiles, as demonstrated by COVID‐19 mRNA vaccines and clinically approved small interfering RNA (siRNA) therapeutics. However, extending RNA delivery beyond the liver to extrahepatic tissues, including the spleen, lungs, lymph nodes, brain, and tumors, remains challenging because of the intrinsic hepatotropism of conventional LNPs and their limited cell‐type specificity. Recent advances in lipid chemistry, particle engineering, surface functionalization, protein corona modulation, and route‐specific administration have enabled new strategies to redirect LNPs toward specific tissues and cell populations. This review systematically examines these approaches and highlights key determinants of LNP tropism, including formulation composition, surface properties, endogenous protein adsorption, and administration route. We further discuss the clinical translation of extrahepatic LNP delivery, covering clinically validated products, emerging therapeutic candidates, and gaps between preclinical models and human applications. Major challenges include cell‐resolved biodistribution, long‐term safety, repeated‐dose immunogenicity, cross‐study comparability, and standardized quantitative assessment. Finally, we explore how high‐throughput screening, machine learning, and data‐driven design can accelerate the rational optimization of next‐generation LNPs. These advances may facilitate precise tissue‐ and cell‐selective RNA delivery, expanding the therapeutic potential of RNA medicines beyond the liver.