The elevated
glutathione (GSH) level in solid
tumors has been used as a major hallmark for GSH-responsive nanoparticles to enhance targeting efficiency and specificity. Meanwhile, GSH is mainly synthesized inside the hepatocytes of the liver in the body and constantly released into the blood through hepatic GSH efflux to regulate redox potential of the entire body. However, it remains largely unknown how this hepatic GSH efflux affects the
tumor targeting of GSH-responsive nanoparticles. Herein, we report that depletion of hepatic GSH enhanced the
tumor targeting of GSH-responsive
indocyanine green-conjugated Au25 nanoclusters coated with 18 GSH
ligand (ICG-Au25 SG18 ). The dissociation of ICG from Au25 SG18 by the hepatic GSH through
thiol-exchange reaction and the subsequent hepatobiliary clearance of the detached ICG were slowed down by GSH depletion, which in turn prolonged the blood circulation of intact ICG-Au25 SG18 and enhanced its
tumor targeting. Our work highlights
glutathione-mediated crosstalk between the liver and
tumor, in addition to well-known Kupffer cell-mediated uptake, in the
tumor targeting of engineered nanoparticles, which could be modulated to enhance targeting efficiency and specificity of
cancer nanomedicines while reducing their nonspecific accumulation.