Application of iron oxide nanoparticles in liver drug delivery: insights into biodegradation and toxicity at cellular, tissue, and organ levels

INTRODUCTION Due to its unique anatomical and physiological properties, the liver is known to capture the prevailing amount of intravenously administered nanoparticles. However, selectively delivering them to hepatocytes, the primary cells affected in most liver diseases, remains challenging, as nanoparticles are predominantly internalized by Kupffer cells, triggering inflammatory responses and fibrosis. Iron oxide nanoparticles can be engineered for active hepatocyte targeting via surface ligand modification, taking into account the nanoparticle size.

AREAS COVERED This review covers the interactions between iron oxide nanoparticles, Kupffer cells, hepatic stellate cells, and hepatocytes. Iron oxide nanoparticles may induce hepatocellular toxicity through mechanisms such as oxidative stress, lysosomal and mitochondrial dysfunction, endoplasmic reticulum stress, and autophagy impairment. Furthermore, iron metabolism and some proteins involved in the regulation of iron homeostasis are also addressed. The role of the Z-potential, size, and surface modification of nanoparticles were analyzed from the point of view of their uptake by liver cells. The corona and margination effects for iron oxide nanoparticles were considered.

EXPERT OPINION Iron oxide nanoparticles hold significant potential for targeted hepatocyte delivery, provided that their physicochemical properties are carefully optimized to minimize off-target uptake by Kupffer cells and reduce hepatotoxicity. A comprehensive understanding of nanoparticle - cell interactions, iron homeostasis, and the impact of surface engineering is essential for the rational design of safer and more effective nanocarriers. Future progress will depend on balancing hepatocyte-specific targeting with biocompatibility, enabling the translational application of iron oxide nanoparticles in the diagnosis and treatment of liver diseases.