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.