Lipid nanoparticles (LNPs) have emerged as a leading platform for the delivery of nucleic acid-based therapeutics, enabling precise modulation of gene expression for the treatment of genetic disorders, cancers, viral infections, and metabolic diseases. Advances in LNP technology have led to rapid clinical translation, exemplified by the success of COVID-19 mRNA vaccines, which demonstrate efficient cellular uptake, robust protein expression, and safety in humans. However, overcoming the intrinsic hepatic tropism of current clinical LNPs remains the foremost barrier to expanding delivery to extrahepatic tissues and cells. This Review examines advanced strategies to achieve extrahepatic, tissue-, and cell-specific delivery. We highlight systematic LNP engineering approaches, including formula optimization, surface physicochemical modifications, ligand conjugation, and administration routes. We further discuss critical translational opportunities and challenges of LNP-mediated targeted nucleic acid delivery, including physiological barriers and species-specific differences, and immune responses. Finally, we outline how the convergence of emerging strategies, such as human organ-on-chip models, species-agnostic nanoparticle screening, and artificial intelligence (AI)-driven design, can accelerate the rational development of next-generation LNPs for highly precise and safe nucleic acid delivery.