Rapid Biotransformation of Luminescent Bimetallic Nanoparticles in Hepatic Sinusoids

Liver sequestration, mainly resulting from the phagocytosis of mononuclear phagocyte system (MPS) cells, is a long-standing barrier in nanoparticle delivery, which severely decreases the disease-targeting ability, leads to nanotoxicity, and inhibits clinical translation. To avoid long-term liver sequestration, we elaborately designed luminescent gold–silver bimetallic nanoparticles that could be rapidly transformed by the hepatic sinusoidal microenvironment rich in glutathione and oxygen, significantly different from monometallic gold nanoparticles that were rapidly sequestrated by Kupffer cells due to the much slower biotransformation. We found that the rapid sinusoidal biotransformation induced by the synergistic reactions of glutathione and oxygen with the reactive silver atoms could help bimetallic nanoparticles to avoid MPS phagocytosis, promote fast release from the liver, prolong blood circulation, enhance renal clearance, and increase disease targeting. With the fast biotransformation in sinusoids, liver sequestration could be turned into a beneficial storage mechanism for nanomedicines to maximize targeting.