This review focuses on the development and optimization of lipid nanoparticles (LNPs) for organ-selective nucleic acid delivery in vivo. LNPs, known for their simple preparation, high stability, and efficient cellular uptake, are widely used as delivery vectors for nucleic acids such as mRNA and siRNA. However, their extensive hepatic accumulation poses a significant challenge for treating extrahepatic diseases. To address this issue, researchers have been modifying the surface properties of LNPs to achieve precise organ targeting. The review covers the general design principles, targeting mechanisms, and clinical development of organ-selective LNPs, providing valuable insights and guidance for further research and development in this field. Key strategies include rational lipid composition, ligand modification, and the SORT (selective organ-targeting) technology, which involves incorporating complementary components to fine-tune the biophysical properties of LNPs for specific organ targeting. The review also highlights the challenges and recent advancements in targeting specific organs such as the liver, lungs, spleen, lymph nodes, brain, and heart, emphasizing the potential of LNPs in treating a wide range of diseases.This review focuses on the development and optimization of lipid nanoparticles (LNPs) for organ-selective nucleic acid delivery in vivo. LNPs, known for their simple preparation, high stability, and efficient cellular uptake, are widely used as delivery vectors for nucleic acids such as mRNA and siRNA. However, their extensive hepatic accumulation poses a significant challenge for treating extrahepatic diseases. To address this issue, researchers have been modifying the surface properties of LNPs to achieve precise organ targeting. The review covers the general design principles, targeting mechanisms, and clinical development of organ-selective LNPs, providing valuable insights and guidance for further research and development in this field. Key strategies include rational lipid composition, ligand modification, and the SORT (selective organ-targeting) technology, which involves incorporating complementary components to fine-tune the biophysical properties of LNPs for specific organ targeting. The review also highlights the challenges and recent advancements in targeting specific organs such as the liver, lungs, spleen, lymph nodes, brain, and heart, emphasizing the potential of LNPs in treating a wide range of diseases.