Liver macrophages capture circulating nanoparticles and reduce their delivery to target organs. Serum proteins adsorb to the nanoparticle surface after administration. However, the adsorbed serum proteins and their cognate cell receptors for removing nanoparticles from the bloodstream have not been linked. Here we use a multi-omics strategy to identify the adsorbed serum proteins binding to specific liver macrophage receptors. We discovered six absorbed serum proteins that bind to two liver macrophage receptors. Nanoparticle physicochemical properties can affect the degree of the six serum proteins adsorbing to the surface, the probability of binding to cell receptors and whether the liver removes the nanoparticle from circulation. Identifying the six adsorbed proteins allowed us to engineer decoy nanoparticles that prime the liver to take up fewer therapeutic nanoparticles, enabling more nanoparticles for targeting extrahepatic tissues. Elucidating the molecular interactions governing the nanoparticle journey in vivo will enable us to control nanoparticle delivery to diseased tissues.