Fe2O3 nanoparticles are absorbed via the CLEC4E-mediated endocytosis in the intestine and via the LDLR/TFR1-mediated endocytosis in the liver of yellow catfish Pelteobagrus fulvidraco

The uptake of nanoparticles (NPs) in the intestine and liver is influenced by their biological milieu. However, the role of biomolecular corona in governing NPs uptake remained elusive. Here, we deciphered the composition of biomolecular corona on Fe2O3 NPs’ surface in the intestine. We identified a membrane protein, C-type lectin domain family 4E-like (CLEC4E), as a critical contributor to intestinal Fe2O3 NPs uptake. Mechanistically, CLEC4E mediated the internalization of Fe2O3 NPs in a clathrin- and caveolae-independent endocytic pathway. Additionally, we characterized the composition of serum protein corona on Fe2O3 NPs’ surface, and identified key ligands (apolipoprotein Eb, complement C8 alpha chain, complement C8 beta chain, apolipoprotein B-100, and serotransferrin-2 isoform X4) related to endocytosis. 69% and 21% of Fe2O3 NPs biodistribution among the six tested tissues could be explained by low-density lipoprotein receptor (LDLR) and transferrin receptor 1 (TFR1) expression, respectively. Mechanistically, LDLR and TFR1 mediated the internalization of Fe2O3 NPs, which was via clathrin-dependent endocytosis. For the first time, our studies show that the Fe2O3 NPs are covered by different biomolecular coronas in the intestine and liver and are accordingly internalized via distinct tissue-specific mechanisms. Our results are helpful for nanoparticle toxicological evaluation and environmental risk assessment in aquatic ecosystem.