Emerging vesicular nanosystems capable of effectively targeting hepatocytes

Liver indications are increasing in prevalence globally, with nanomedicines emerging as a potential treatment strategy. Hepatocytes play an important role in most liver diseases, making the ability to target these cells an important consideration in the development of therapeutics. Although nanomedicines administered intravenously do tend to accumulate in the liver thanks to its high blood flow, specifically targeting hepatocytes remains non-trivial due to several aspects of liver physiology. For example, hepatocytes are challenging to reach within the liver tissue due to limited fenestrae size in the liver vessels. Disease and age further reduce fenestration, meaning that optimal therapeutic effect is difficult to achieve. To overcome these obstacles, different nanomedicines have been rationally designed to possess optimized size and surface properties, along with hepatocyte-specific targeting ligands. This review discusses developments in vesicular nanotechnologies published in English since 2022, within the context of the unique challenges presented by hepatocyte delivery. The lipid nanoparticles, liposomes, niosomes, and lipid calcium phosphate nanoparticles discussed, from pre-clinical research to clinically approved treatments, represent significant advancements toward this goal. However, further challenges remain, and we expect to continue to see advancements in model development and novel nanosystems tailored for effectiveness in diseased states.