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The successful delivery of nanoparticles to solid tumors depends on their ability to pass through blood vessels and into the tumor microenvironment. Here, we discovered a subset of tumor endothelial cells that facilitate nanoparticle transport into solid tumors. We named these cells nanoparticle transport endothelial cells (N-TECs). We show that only 21% of tumor endothelial cells located on a small number of vessels are involved in transporting nanoparticles into the tumor microenvironment. N-TECs have an increased expression of genes related to nanoparticle transport and vessel permeability compared to other tumor endothelial cells. The N-TECs act as gatekeepers that determine the entry point, distribution, cell accessibility, and number of nanoparticles that enter the tumor microenvironment.

Nanoparticles need to navigate a complex microenvironment to target cells in solid tumors after extravasation. Diffusion is currently the accepted primary mechanism for nanoparticle distribution in tumors. However, the extracellular matrix can limit nanoparticle diffusion. Here, we identified tumor-associated macrophages as another key player in transporting and redistributing nanoparticles in the tumor microenvironment. We found tumor-associated macrophages actively migrate toward nanoparticles extravasated from the vessels, engulfing and redistributing them in the tumor stroma. The macrophages can carry the nanoparticles 2–5 times deeper in the tumor than passive diffusion. The amount of nanoparticles transported by the tumor-associated macrophages is size-dependent. Understanding the nanoparticle behavior after extravasation will provide strategies to engineer them to navigate the microenvironment for improved intratumoral targeting and therapeutic effectiveness.

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