Selective organ-targeting (SORT) lipid nanoparticles (LNPs) have emerged as a transformative platform in precision medicine, enabling efficient and safe delivery of therapeutic agents to specific organs. This review explores the mechanistic foundations, design strategies, and biomedical applications of SORT LNPs. Key targeting mechanisms include dynamic protein corona formation, which mediates tissue-specific uptake through endogenous interactions, and the rational modulation of nanoparticle size, surface chemistry, and material composition to manipulate in vivo biodistribution. Recent advancements highlight targeted delivery systems for the liver, lungs, and spleen, leveraging both passive and active targeting as well as endogenous cues. Despite the clinical success of mRNA and siRNA therapies, challenges such as immunogenicity, biodistribution complexity, and interspecies translation remain. This review provides a comprehensive overview of SORT development, offering insights into the next generation of intelligent, biocompatible, and organ-specific nanomedicines for cancer and immune-related diseases.