Priming the Liver Endocytic Pathway to Accelerate Hepatobiliary Clearance of Nanoparticles

Prolonged hepatic accumulation represents a major obstacle for clinical translation of many nanomedicines, particularly for those not easily biodegradable. While many strategies such as PEGylation have been developed to reduce or delay the liver uptake of nanoparticles, strategies that expedite nanoparticle elimination after liver uptake are rarely reported. Herein, we report a broadly applicable strategy to accelerate hepatobiliary elimination of diverse nanoparticles through priming of the liver endocytic pathway. Inspired by our findings that smaller gold nanoparticles exhibit inherently faster hepatobiliary clearance due to size-dependent endocytic pathways, we discovered that inhibition of clathrin-mediated endocytosis (CME) significantly enhances nanoparticle exocytosis from hepatocytes and macrophages. Mechanistically, we found that CME inhibition alters nanoparticle intracellular trafficking, diverting endocytosed nanoparticles from the lysosomal pathway to the Golgi apparatus for faster exocytosis. Using the clinically approved drug chlorpromazine as a CME inhibitor, we demonstrated that priming the liver with chlorpromazine markedly accelerated hepatobiliary clearance and reduced hepatic retention of various nanoparticles ranging from inorganic to organic ones in mice. Moreover, in a murine tumor model, we showed that hepatic CME inhibition accelerated hepatobiliary elimination of the model nanomedicine without compromising its disease targeting efficacy. Our discovery highlights a versatile strategy for accelerating hepatobiliary elimination of nanoparticles, which is expected to synergize with previous strategies for overcoming nonspecific liver accumulation of nanomedicines.