This review discusses the development of optimized lipid nanoparticles (LNPs) for organ-selective delivery of nucleic acids in vivo. Nucleic acid therapeutics, such as mRNA and siRNA, hold great promise for treating a wide range of diseases, but their in vivo delivery faces significant biological barriers. LNPs are promising delivery vectors due to their advantages, including simple preparation, high stability, efficient cellular uptake, and endosomal escape capabilities. However, their tendency to accumulate in the liver poses challenges for extrahepatic disease treatments. To address this, researchers have focused on modifying LNPs to achieve precise delivery to specific organs. The review highlights current strategies for organ-selective LNPs, including the design principles, targeting mechanisms, and clinical development. It discusses various approaches for targeting different organs, such as the liver, lung, spleen, lymph nodes, brain, and heart. For example, liver-targeting LNPs can be enhanced by optimizing lipid composition and using ligands like GalNAc to target hepatocytes. Lung-targeting LNPs can be improved by using cationic helper lipids and optimizing physicochemical properties. Spleen-targeting LNPs can be achieved through the use of specific ligands and the SORT technology. Lymph node-targeting LNPs can be enhanced by using adjuvants like Pam2Cys to induce immune responses. Brain-targeting LNPs can be developed by using ligands that cross the blood-brain barrier. Heart-targeting LNPs are challenging due to the limited ability of LNPs to target cardiac cells, but recent studies have shown promising results. Other organs, such as the eye and fetus, also have specific targeting strategies. The review emphasizes the importance of understanding the physicochemical properties of LNPs, including charge, size, pKa, and the structure of key lipids, to achieve precise targeting. It also highlights the role of ligand modifications and the use of advanced screening techniques to identify optimal LNPs for specific organ targeting. Overall, the review provides a comprehensive overview of the current state of organ-selective LNPs and their potential for future research and clinical applications.This review discusses the development of optimized lipid nanoparticles (LNPs) for organ-selective delivery of nucleic acids in vivo. Nucleic acid therapeutics, such as mRNA and siRNA, hold great promise for treating a wide range of diseases, but their in vivo delivery faces significant biological barriers. LNPs are promising delivery vectors due to their advantages, including simple preparation, high stability, efficient cellular uptake, and endosomal escape capabilities. However, their tendency to accumulate in the liver poses challenges for extrahepatic disease treatments. To address this, researchers have focused on modifying LNPs to achieve precise delivery to specific organs. The review highlights current strategies for organ-selective LNPs, including the design principles, targeting mechanisms, and clinical development. It discusses various approaches for targeting different organs, such as the liver, lung, spleen, lymph nodes, brain, and heart. For example, liver-targeting LNPs can be enhanced by optimizing lipid composition and using ligands like GalNAc to target hepatocytes. Lung-targeting LNPs can be improved by using cationic helper lipids and optimizing physicochemical properties. Spleen-targeting LNPs can be achieved through the use of specific ligands and the SORT technology. Lymph node-targeting LNPs can be enhanced by using adjuvants like Pam2Cys to induce immune responses. Brain-targeting LNPs can be developed by using ligands that cross the blood-brain barrier. Heart-targeting LNPs are challenging due to the limited ability of LNPs to target cardiac cells, but recent studies have shown promising results. Other organs, such as the eye and fetus, also have specific targeting strategies. The review emphasizes the importance of understanding the physicochemical properties of LNPs, including charge, size, pKa, and the structure of key lipids, to achieve precise targeting. It also highlights the role of ligand modifications and the use of advanced screening techniques to identify optimal LNPs for specific organ targeting. Overall, the review provides a comprehensive overview of the current state of organ-selective LNPs and their potential for future research and clinical applications.