Hepatotoxicity of Nanoparticle-Based Anti-Cancer Drugs: Insights into Toxicity and Mitigation Strategies

Despite significant progress in developing novel, efficient nanoparticle-based anticancer drugs, hepatotoxicity remains a major challenge. The liver, as the primary organ responsible for detoxification, is particularly susceptible to nanoparticle accumulation, particularly through the action of Browicz-Kupffer cells (B-KCs) and liver sinusoidal endothelial cells (LSECs). These phagocytic cells accumulate nanoparticles, leading to the production of reactive oxygen species (ROS), interleukin 1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α), which ultimately cause hepatocyte damage. In recent years, various nanoparticle modification strategies have been investigated to reduce hepatotoxicity. One of the most common and effective approaches is the PEGylation of liposomes and graphene nanoparticles, which decreases their uptake by the liver via the reticuloendothelial system (RES). Other strategies to mitigate hepatotoxicity are also being explored, including the incorporation of negatively charged lipids into liposomes, charge manipulation of inorganic-organic nanoparticles, the use of specific protein-based nanoparticles that selectively bind to cancer cells (thereby reducing hepatic uptake), the use of appropriate viral capsids in the production of virus-like protein-based drugs, and the manipulation of the size of protein, metal and graphene nanoparticles. Moreover, modifications aimed at pH-responsive drug release are employed in liposomes, self-assembled and graphene nanoparticles. This article discusses several types of nanoparticles used as carriers in currently approved therapies and explores potential strategies to minimize their hepatotoxicity.