Unintended biodistribution of biologics can pose significant toxicological challenges. Antibody fragments used as carriers for cytotoxic payloads, such as in radiotherapy or antibody-drug conjugates, may accumulate in clearance organs and within the reticuloendothelial system (RES), leading to dose-limiting toxicities. This risk is particularly elevated for antibodies and antibody fragments lacking Fc Neonatal Receptor (FcRn) mediated recycling, where internalized proteins are degraded rather than returned to circulation. As the industry explores diverse therapeutic formats, including advanced biologics that lack FcRn-mediated recycling, understanding the mechanisms of endothelial cell endocytosis is critical to mitigating off-target uptake. We present findings that deepen our understanding of the molecular mechanisms underlying fluid-phase endocytosis within the reticuloendothelial system and introduce a novel strategy to minimize uptake in healthy organs in favor of tumor targeting.