Ligand-dependent pharmacokinetic modulation via copper doping in ultrasmall gold nanoparticles

Ultrasmall gold nanoparticles (AuNPs, <3 nm) exhibit great potential for precision nanomedicine. While ligand engineering and core doping have each been explored to enhance their performance, whether surface chemistry dictates the in vivo efficacy of alloyed nanoparticles remains unknown. To address this question, we used glutathione (GSH) and polyethylene glycol (PEG) as model stabilizing ligands, systematically comparing four corresponding nanoparticle groups: GSH-coated or PEGylated AuNPs, each with or without copper doping at comparable levels. Strikingly, copper doping induced negligible pharmacokinetic changes in PEGylated nanoparticles but significantly enhanced GSH-coated nanoparticles. GS-AuCuNPs exhibited significantly enhanced pharmacokinetics compared to undoped GS-AuNPs, with a 1.6-fold increase in the area under the plasma concentration-time curve. Tumor accumulation efficiency improved by 1.6-fold at 1 h and 1.5-fold at 12 h post-injection, accompanied by reduced renal excretion. This ligand-specific enhancement arises from a copper-induced interfacial reconfiguration, characterized by enhanced COO^--metal anchoring and increased exposure of -NH₂ groups of GSH, which together increase the surface positive charge. These interfacial changes modulate nanoparticle-biological interactions, resulting in prolonged circulation and reduced renal excretion while preserving the intrinsic clearance pathway. Our findings reveal a core-ligand coupling principle whereby metal doping becomes pharmacokinetically effective only when paired with a chemically synergistic ligand shell.