Glutathione-mediated biotransformation in the liver modulates nanoparticle transport

Glutathione-mediated biotransformation in the liver is a well-known detoxification process to eliminate small xenobiotics but its impacts on nanoparticle retention, targeting and clearance are much less understood than liver macrophage uptake even though both processes are involved in the liver detoxification. By designing a thiol-activatable fluorescent gold nanoprobe that can bind to serum protein and be transported to the liver, we noninvasively imaged this biotransformation kinetics in vivo at high specificity and examined this process at the chemical level. Our results show that glutathione efflux from hepatocytes resulted in high local concentrations of both glutathione and cysteine in liver sinusoids, which transformed the nanoparticle surface chemistry, reduced its affinity to serum protein and significantly altered its blood retention, targeting and clearance. With this biotransformation, liver detoxification, a long-standing barrier in nanomedicine translation, can be turned into a bridge toward maximizing targeting and minimizing nanotoxicity.