Long-term accumulation in the liver is a major obstacle for the clinical translation of many nanomedicines, especially those that are not easily biodegradable. Although several strategies such as PEGylation have been developed to reduce or delay the absorption of nanoparticles by the liver, strategies for accelerating the elimination of nanoparticles after liver absorption have rarely been reported. This paper reports a broadly applicable strategy that accelerates the elimination of various nanoparticles in the liver and bile ducts by activating the endocytic pathway within the liver. Inspired by our discovery that smaller gold nanoparticles are inherently cleared faster in the liver and bile ducts due to size-dependent endocytic pathways, we found that inhibiting the endocytosis mediated by clathrin (CME) significantly enhanced the nanoparticle exocytosis in hepatocytes and macrophages. Mechanistically, we found that CME inhibition alters the intracellular transport of nanoparticles, redirecting the endocytosed nanoparticles from the lysosomal pathway to the Golgi apparatus, thereby accelerating the exocytosis rate. We used the clinically approved drug chlorpromazine as a CME inhibitor and demonstrated that activating the liver with chlorpromazine significantly accelerated liver and bile duct clearance and reduced liver retention of various nanoparticles (from inorganic to organic) in mice. Additionally, in a mouse tumor model, we demonstrated that liver CME inhibition accelerated the elimination of the model nanomedicine liver-bile pathway and did not affect its disease-targeting efficacy. Our findings highlight a flexible strategy for accelerating the elimination of nanoparticles in the liver and bile ducts, which is expected to synergize with previous strategies for overcoming the non-specific liver accumulation of nanomedicines. References: DOI: 10.1021/acsnano.5c20532