Timely lysosome escape is very important for nanomedicines to avoid premature degradation. Herein, we report an exciting finding that phenylboronic acid (PBA) modification can greatly facilitate the lysosome escape of cylindrical polymer brushes (CPBs), and further promote their exocytosis and transcellular transfer. This fundamental finding for the first time reveals that PBA groups improve the tumor penetration of nanomaterials via an active transcytosis mechanism. We speculate that the mechanism of the PBA-enhanced lysosome escape is associated with the specific interactions of the PBA group with the lysosomal membrane proteins and hot shock proteins. The featured advantage of the PBA modification over the known lysosome escape strategies is that it does not cause significant adverse effects on the properties of the CPBs. Furthermore, doxorubicin was conjugated to the PBA-modified CPBs with drug loading content larger than 20%. This CPBs-based prodrug could eradicate the tumors established in mice by multiple intravenous administration.