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 nanomedicines, 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 confer 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 clinical translation.

外渗是循环中的纳米药物到达靶向实体瘤的第一步。传统的纳米药物被设计成通过先前假定富含肿瘤血管的内皮间隙渗入肿瘤间质，即增强的通透性和保留（EPR）效应。虽然 EPR 效应已在动物异种移植肿瘤模型中得到验证，但越来越多的证据表明 EPR 效应在人类肿瘤中非常有限且高度异质，导致高度不可预测和低效的外渗，从而限制了纳米药物的治疗效果，包括那些在临床上批准的药物. 实现不依赖 EPR 的外渗是开发具有增强疗效的新一代纳米药物的关键。肿瘤内皮细胞的胞吞作用可以使纳米药物在不依赖 EPR 效应的情况下主动外渗到实体瘤中。在这里，我们回顾和展望 诱导转胞吞作用的纳米药物的开发，希望为设计能够通过肿瘤内皮细胞进行选择性跨细胞转运的纳米药物提供指导性见解，从而激发用于临床转化的下一代纳米药物的开发。