Liver sinusoidal endothelium mediates systemic clearance of ultrasmall gold nanoparticles through secretion of circulating exosomes.

Liver sinusoidal endothelium featuring a unique discontinuous lining and robust endocytic activity is vital for nanoparticle retention, clearance, and translocation. However, liver sinusoidal endothelium-mediated nanoparticle elimination remains far less understood than liver macrophage uptake despite both processes being involved in hepatic detoxification. Using water-soluble Au 25 ( o -MBA) 18 ( o -MBA: o -mercaptobenzoic acids) with optimized local hydrophobicity for weak protein-binding affinity and high endothelium targeting as probes, we report an exosome-mediated systemic clearance for endocytosed nanoclusters in sinusoidal endothelial cells. Au 25 ( o -MBA) 18 can effectively avoid phagocytosis by liver macrophage, are initially endocytosed by sinusoidal endothelial cells through clathrin-dependent endocytosis, processed through endosomal pathways, and released as exosomes containing nanoclusters into the bloodstream. During the exosome biogenesis, Au 25 ( o -MBA) 18 progressively transform into flower-like aggregates (approximately 100 nm). These circulating exosomes traverse the glomerular membrane through autophagy in glomerular endothelial cells and podocytes before urinary excretion. Here, this exosome-mediated pathway converts exogenous ultrasmall gold nanoparticles into biocompatible endogenous exosome-enveloped cargos for systemic circulation with reduced toxicity, providing a foundation for developing next generation of safe and effective nanomedicines.