Boosting Cellular Glutathione Accelerates Elimination of Engineered Ultrasmall Nanoparticles from Kidneys and Liver by Promoting Exosome Release.

Being two major detoxifying organs for in vivo clearance of nanoparticles, the kidneys and liver are susceptible to prolonged accumulation of engineered nanoparticles and associated side effects, particularly for the nondegradable ones. Thus, strategies that expedite the elimination of accumulated nanoparticles from these organs are in high demand. Herein, using two engineered ultrasmall gold nanoparticles that respectively accumulate in the kidneys and liver as models, we showed that orally supplementing N-acetylcysteine (NAC), a clinical drug and precursor of glutathione (GSH), significantly accelerated the elimination of accumulated ultrasmall gold nanoparticles in the kidneys and liver while promoting their renal and hepatobiliary excretion in mice. This enhanced elimination effect stemmed from NAC-induced elevation of intracellular GSH levels, which facilitates endocytosed ultrasmall nanoparticles to be exocytosed via exosomes instead of prolonged trapping in the lysosomes, a mechanism distinct from the conventional transporter-mediated export of small-molecule xenobiotics through GSH conjugation. Moreover, this promotion of exosome release was found to be independent of nanoparticle treatment but a natural cellular response to boosted GSH levels by NAC. Our findings thus demonstrate NAC supplementation as a potential strategy for accelerating the excretion of ultrasmall nanoparticles from the kidneys and liver, offering insights into the role of GSH in facilitating cellular elimination of substances.