Stealthy nanoparticles protect endothelial barrier from leakiness by resisting the absorption of VE-cadherin.

Nanomaterial induced endothelial cell leakiness (NanoEL) is caused because nanomaterials enter the interstitial space of the endothelial cells and disrupt the endothelial cell-cell interactions by interacting with vascular endothelial cadherin (VE-cad). Whereas the NanoEL effect could cause controllable leakiness in cancer therapy, the gaps created by the NanoEL effect can make the cancer cells cross the endothelial barrier and produce side effects induced by using nanomedicine. In this paper, a series of ultralow protein corona nanoparticle is reported that can penetrate the endothelial cell junction without obviously interacting with the VE-cad and phosphorylating the tyrosine 658 (Y658) and tyrosine 731 (Y731) residues on VE-cad, thus preventing the VE-cad from being activated by Src kinase, and this avoids inducing of the NanoEL effect and cancer cell migration, regardless of particle material, density and surface charge. These findings provide a new idea for the design of novel nanoparticles without side effects and can maximize their cancer-killing effect.