Transcytosis-enabled active extravasation of tumor nanomedicine

Extravasation is the first step for nanomedicines in circulation to reach targeted solid tumors. Traditional nanomedicines have been designed to extravasate into tumor interstitium through the interendothelial gaps previously assumed rich in tumor blood vessels, i.e., the enhanced permeability and retention (EPR) effect. While the EPR effect has been validated in animal xenograft tumor models, accumulating evidence implies that the EPR effect is very limited and highly heterogeneous in human tumors, leading to highly unpredictable and inefficient extravasation and thus limited therapeutic efficacy of nanomedici-nes, including those approved in clinics. Enabling EPR-independent extravasation is the key to develop new generation of nanomedicine with enhanced efficacy. Transcytosis of tumor endothelial cells can con-fer nanomedicines to actively extravasate into solid tumors without relying on the EPR effect. Here, we review and prospect the development of transcytosis-inducing nanomedicines, in hope of providing instructive insights for design of nanomedicines that can undergo selective transcellular transport across tumor endothelial cells, and thus inspiring the development of next-generation nanomedicines for clin-ical translation.(c) 2022 Elsevier B.V. All rights reserved.

Automated summary

Extravasation is the crucial process for nanomedicines to reach solid tumors. However, the Enhanced Permeability and Retention (EPR) effect, which was previously considered as the primary extravasation mechanism, is limited and heterogeneous in human tumors. To overcome this limitation and enhance therapeutic efficacy, the development of transcytosis-inducing nanomedicines has been proposed. These nanomedicines can actively extravasate into solid tumors by utilizing the transcellular transport mechanism of tumor endothelial cells.