A longstanding and widely accepted bottleneck in the targeted delivery of intravenously injected nanoparticles lies in their clearance by macrophages in the liver and spleen. In this Perspective, we call for deeper understanding of the critical role of endothelial cells in the sequestration of nanoparticles in vivo. In this issue of ACS Nano, Campbell et al. used a combination of real-time imaging and genome-editing methods to demonstrate that stabilin-2 is an important receptor for removing anionic liposomes from blood circulation in a zebrafish model. Such mechanistic insights at the molecular level will provide a more holistic picture of the in vivo sequestration of administered nanoparticles beyond the cellular level and pose valuable design considerations for redistributing nanoparticles in vivo.