Enhanced transendothelial delivery of albumin-based carriers into tumors via macropinocytosis.

Macropinocytosis is an endocytic pathway that allows tumor cells to internalize extracellular proteins, making albumin a promising carrier for anti-tumor drug delivery. However, how albumin-based carriers cross the vascular barrier to enter solid tumors remains unclear. Here, we show that macropinocytosis in tumor endothelial cells (TECs) contributes to the active transendothelial transport of albumin-based carriers into tumors. Inhibition of macropinocytosis reduced their intratumoral accumulation by more than 60%. Furthermore, we show that tumor-derived vascular endothelial growth factor (VEGF) activates the Rho GTPase CDC42 in TECs, driving actin cytoskeletal remodeling and macropinosome formation, thus facilitating transendothelial transport of the payload. These findings identify VEGF-CDC42-driven endothelial macropinocytosis as an active transport mechanism that contributes to macromolecular delivery into tumors, offering a framework for the rational design of albumin-based drug delivery systems.