Physics-driven mechanisms governing the pharmacokinetics and immune fate of gold nanoparticles. I. An ADIE framework perspective

Gold nanoparticles’ (GNPs) clinical translation requires a mechanistic understanding of their pharmacokinetics at the nano–bio interface. Classical ADME (Absorption, Distribution, Metabolism, Elimination) models describe biodegradable materials but do not capture the behavior of inorganic nanomaterials. The in vivo fate of GNPs is governed not by metabolic biochemistry but by transport physics, interfacial energetics (thermodynamics), and corona-encoded biological recognition. This Perspective introduces the ADIE (Absorption, Distribution, Interaction, Elimination) framework, in which Interaction becomes the central determinant of nanoparticle fate. Distribution reflects convection and diffusion transport, while Brownian motion and thermodynamics drive protein corona (PC) formation. The composition of the corona determines which liver cell populations engage each particle, directing GNPs toward Kupffer cells, liver sinusoidal endothelial cells, or hepatocytes through receptor-based pathways. Interaction is defined as the combined processes of biotagging (adsorption of PC that assigns each particle a biological identity) and biorecognition (receptor-mediated engagement of that identity by immune and non-immune liver cells). Within ADIE, Interaction replaces Metabolism because GNPs undergo biotagging rather than biochemical transformation. Elimination depends on size and uptake route. Ultrasmall GNPs below 6 nm undergo renal filtration, whereas larger or non-stealth particles enter hepatic processing. Kupffer cell uptake results in immune sequestration; LSEC uptake leads to endothelial retention; hepatocyte uptake enables limited biliary elimination in which a small fraction of intact GNPs is transported to the canalicular membrane for fecal excretion. Thus, the liver functions primarily as a retention organ but also provides a minor excretory pathway. This physics-driven Perspective (Paper I) establishes the mechanistic foundations of ADIE and explains how nano–bio interactions govern GNP fate. The companion article (Paper II) extends these principles to broader pharmacokinetic implications for nanoparticle biodistribution, retention, clearance, and design.