Organ-Selective Lipid Nanoparticles: A Landscape Review of Mechanisms, Applications, and Translational Challenges

Abstract Lipid nanoparticles (LNPs) are the dominant clinical platform for nucleic acid delivery, as shown by liver-directed patisiran and intramuscular mRNA-based COVID-19 vaccines. Neither involved engineered organ selectivity. Conventional four-component LNPs accumulate mainly in the liver after systemic administration, which limits their use to hepatocyte-targeted therapies. Selective organ targeting (SORT) adds a fifth, charged “SORT lipid” to the formulation. This redirects payloads to the lung, spleen, or liver in a predictable, dose-titratable manner. The leading proposed explanation is that SORT lipid alters the protein corona that forms in blood, shifting uptake away from the apolipoprotein E–low-density lipoprotein receptor pathway behind default hepatic accumulation. Consensus on this mechanism is lacking. Lipid charge and pKa, route-dependent hemodynamics, and vascular fenestration may contribute independently or in combination. We review mechanistic and translational evidence for lung-, spleen-, and liver-selective SORT formulations across three tiers: rodent, higher-order preclinical, and clinical or clinical-adjacent. We also cover bone marrow, tumor, and CNS targets and payload-specific demands. A bibliometric analysis of administration routes, corona proteins, cell types, payloads, and diseases complements this synthesis. Research volume concentrates on intravenous delivery, oncology/immunotherapy, and cystic fibrosis. Bone marrow, broader immune cell, and LSEC targeting remains comparatively underexplored. Associations between corona composition and tropism are more robust than demonstrated causality, and most direct evidence still comes from rodents, not primates or humans. We outline translational gaps and propose machine learning-guided lipid screening, combinatorial SORT–ligand targeting, and patient-specific corona profiling as priority directions for extrahepatic gene therapy, in vivo cell engineering, and precision vaccination.