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Cancer nanomedicines predominately rely on transport processes controlled by tumor‐associated endothelial cells to deliver therapeutic and diagnostic payloads into solid tumors. While the dominant role of this class of endothelial cells for nanoparticle transport and tumor delivery is established in animal models, the translational potential in human cells needs exploration. Using primary human breast cancer as a model, the differential interactions of normal and tumor‐associated endothelial cells with clinically relevant nanomedicine formulations are explored and quantified. Primary human breast cancer‐associated endothelial cells exhibit up to ≈2 times higher nanoparticle uptake than normal human mammary microvascular endothelial cells. Super‐resolution imaging studies reveal a significantly higher intracellular vesicle number for tumor‐associated endothelial cells, indicating a substantial increase in cellular transport activities. RNA sequencing and gene expression analysis indicate the upregulation of transport‐related genes, especially motor protein genes, in tumor‐associated endothelial cells. Collectively, the results demonstrate that primary human breast cancer‐associated endothelial cells exhibit enhanced interactions with nanomedicines, suggesting a potentially significant role for these cells in nanoparticle tumor delivery in human patients. Engineering nanoparticles that leverage the translational potential of tumor‐associated endothelial cell‐mediated transport into human solid tumors may lead to the development of safer and more effective clinical cancer nanomedicines.

Most nanomedicines require efficient in vivo delivery to elicit meaningful diagnostic and therapeutic effects. However, en route to their intended tissues, systemically administered nanoparticles often encounter delivery barriers. To describe these barriers, the term “nanoparticle blood removal pathways” (NBRP) is proposed, which summarizes the interactions between nanoparticles and the body's various cell‐dependent and cell‐independent blood clearance mechanisms. Nanoparticle design and biological modulation strategies are reviewed to mitigate nanoparticle‐NBRP interactions. As these interactions affect nanoparticle delivery, the preclinical literature from 2011–2021 is studied, and the nanoparticle blood circulation and organ biodistribution data are analyzed. The findings reveal that nanoparticle surface chemistry affects the in vivo behavior more than other nanoparticle design parameters. Combinatory biological‐PEG surface modification improves the blood area under the curve by ≈418%, with a decrease in liver accumulation of up to 47%. A greater understanding of nanoparticle‐NBRP interactions and associated delivery trends will provide new nanoparticle design and biological modulation strategies for safer, more effective, and more efficient nanomedicines.