Deciphering the Hepatic Cellular Interactions of PEGylated Iron Oxide Nanoparticles

The hepatic accumulation of nanoparticles significantly impedes their diagnostic and therapeutic efficacy in biomedical applications. However, the precise role of specific physicochemical properties in determining nanoliver interaction remains poorly understood. This study utilizes ^99mTc-labeled iron oxide nanoparticles to elucidate the effect of size (3.6 and 12.0 nm) and PEG chain length (1K, 2K, and 5K) on their hepatic interactions. <i>In vivo</i> SPECT/CT imaging reveals that small particles initially clear through the kidneys, while large particles predominantly accumulate in the liver and spleen, ultimately showing significant liver uptake. Longer PEG chains generally extend circulation time and slow hepatic uptake, with particles coated with 2K PEG exhibiting the lowest hepatic accumulation, suggesting an optimal balance between circulation time and hepatic sequestration. Complementary <i>in vitro</i> studies with primary liver cells─namely hepatocytes (HCs), liver sinusoidal endothelial cells (LSECs), Kupffer cells (KCs), and hepatic stellate cells (HSCs)─reveal complex uptake behaviors significantly influenced by particle size and PEG chain length. Contrary to conventional wisdom, the study identifies an uptake trend of HCs ∼ HSCs > LSECs > KCs, challenging the prevailing notion of KCs as the primary mediators of nanoparticle clearance. Bridging <i>in vitro</i> and <i>in vivo</i> observations, the hepatic accumulation of small particles closely correlates with uptake patterns in primary HCs, while the accumulation of large particles is linked to interactions with LSECs and KCs. These results highlight the importance of cellular microenvironments in nanoliver interactions, offering design guidance for optimizing nanomedicines to achieve enhanced specificity and reduced off-target effects.