Abstract
Liver-targeted drug delivery offers opportunities to increase therapeutic exposure at sites of hepatic disease while limiting systemic toxicity; however, successful targeting requires more than preferential accumulation of a carrier within the liver. This narrative review critically summarizes recent advances in synthetic, biological, and biomimetic delivery platforms, including lipid, polymeric, inorganic, and protein-based nanoparticles, nucleic acid nanocarriers, extracellular vesicles, plant-derived nanovesicles, cell-mediated systems, and cell membrane-coated nanoparticles. A literature search was conducted using PubMed, Web of Science, and Embase, with emphasis on studies published during the last decade and updated through 24 August 2026. Particular attention is given to the biological determinants of hepatic biodistribution, including sinusoidal architecture, physicochemical carrier properties, protein corona formation, receptor-ligand interactions, and disease-associated alterations in the hepatic microenvironment. The review distinguishes organ-level hepatic accumulation from cell-specific uptake and productive intracellular delivery and discusses strategies directed toward hepatocytes, hepatic stellate cells, Kupffer cells and other macrophages, liver sinusoidal endothelial cells, neutrophils, and additional immune-cell populations. Major delivery platforms are critically compared with respect to the evidence supporting targeting specificity, cargo compatibility, administration route, reported safety and immunogenicity, manufacturability, analytical characterization, and translational maturity. Particular consideration is given to extracellular vesicle- and plant-derived nanovesicle-based approaches, for which biological activity, biodistribution, standardization, and scalability remain important areas of investigation. Overall, current research in liver-targeted delivery is increasingly focused on moving beyond nonspecific organ accumulation toward disease-adapted, cell-specific, and intracellularly productive delivery, although substantial biological, manufacturing, and regulatory challenges remain before many emerging approaches can achieve routine clinical translation.