Overcoming Hepatic\nBiotransformation Barrier of Gold\nNanoparticles via Au–Se Bond for Enhanced <i>In Vivo</i> Active Targeting

As a key metabolic function of the liver, the hepatic\nbiotransformation\nprocess can alter the predesigned surface chemistry of nanoparticles <i>in vivo</i>, leading to hampered functionality and targeting\nability. However, strategies to modulate the hepatic biotransformation\nof nanoparticles have been rarely explored. Herein, using indocyanine\ngreen (ICG)-conjugated gold nanoparticles that target liver hepatocytes\nas a model, we showed that merely changing the metal–ligand\nbond from gold–sulfur (Au–S) to gold–selenium\n(Au–Se) completely reshaped the hepatic biotransformation profiles\nof the nanoparticle as well as its targeting and transport behaviors <i>in vivo</i>. Compared with those of Au–S bond, Au–Se\nbond markedly slowed down nanoparticle biotransformation in liver\nsinusoids, enhanced ICG-mediated nanoparticle targeting to hepatocytes\nby 15-fold, and also altered nanoparticle intrahepatic transport,\ndistribution, and clearance pathways. Moreover, we demonstrated that\nAu–Se bond could improve the active targeting of gold nanoparticles\nto hepatic tumors by reducing liver biotransformation-induced dissociation\nof targeting ligands. These discoveries not only deepen our understanding\nof nanoparticle biotransformation in the liver but also offer a strategy\nto overcome the biochemical barrier of hepatic biotransformation,\nproviding guidance for the design and engineering of related nanomedicines\nby tuning their <i>in vivo</i> biotransformation profiles.