Hepatic Biotransformation of Renal Clearable Gold Nanoparticles for Noninvasive Detection of Liver Glutathione Level via Urinalysis

Abstract Renal clearable nanoparticles have been drawing much attention as they can avoid prolonged accumulation in the body by efficiently clearing through the kidneys. While much effort has been made to understand their interactions within the kidneys, it remains unclear whether their transport could be influenced by other organs, such as the liver, which plays a crucial role in metabolizing and eliminating both endogenous and exogenous substances through various biotransformation processes. Here, by utilizing renal clearable IRDye800CW conjugated gold nanocluster (800CW 4 ‐GS 18 ‐Au 25 ) as a model, we found that although 800CW 4 ‐GS 18 ‐Au 25 strongly resisted serum‐protein binding and exhibited minimal accumulation in the liver, its surface was still gradually modified by hepatic glutathione‐mediated biotransformation when passing through the liver, resulting in the dissociation of IRDye800CW from Au 25 and biotransformation‐generated fingerprint message of 800CW 4 ‐GS 18 ‐Au 25 in urine, which allowed us to facilely quantify its urinary biotransformation index (UBI) via urine chromatography analysis. Moreover, we observed the linear correlation between UBI and hepatic glutathione concentration, offering us a noninvasive method for quantitative detection of liver glutathione level through a simple urine test. Our discoveries would broaden the fundamental understanding of in vivo transport of nanoparticles and advance the development of urinary probes for noninvasive biodetection.