Nano-induced endothelial leakiness-reversing nanoparticles for targeting, penetration and restoration of endothelial cell barrier

Nano-induced endothelial leakiness (NanoEL) can improve the ability of nanoparticles (NPs) to enter the tumor environment, nevertheless, it can inadvertently trigger adverse effects such as tumor metastasis. To overcome these concerns, it becomes important to develop a NPs design strategy that capitalizes on the NanoEL effect while averting unwanted side effects during the drug delivery process. Herein, we introduce the PLGA-ICG-PEI-Ang1@M NP which has a core comprising poly (lactic-co-glycolic acid) (PLGA) and the inner shell with a highly positively charged polyethyleneimine (PEI) and the anti-permeability growth factor Angiopoietin 1 (Ang1), while the outer shell is camouflaged with a Jurkat cell membrane. During the drug delivery process, our NPs exhibit their capability to selectively target and penetrate endothelial cell layers. Once the NPs penetrate the endothelial layer, the proton sponge effect triggered by PEI in the acidic environment surrounding the tumor site can rupture the cell membrane on the NPs' surface. This rupture, in turn, enables the positively charged Ang1 to be released due to the electrostatic repulsion from PEI and the disrupted endothelial layer can be restored. Consequently, the designed NPs can penetrate endothelial layers, promote the cell layer recovery, restrict the tumor metastasis, and facilitate efficient cancer therapy. This work develops a NP design strategy that capitalizes on the nano-induced endothelial leakiness (NanoEL) effect while averting unwanted side effects such as tumor metastasis during the drug delivery process. The rational design of core-double shell PLGA-ICG-PEI-Ang1@M NP enables enhanced drug transport across the endothelial barrier inherited from both membrane-derived tumor homing and NanoEL effect brought by NPs. The controlled release of angiopoietin-1 in response to the tumor microenvironment allows a timely recovery of endothelial cell leakiness which can avert unwanted side effects due to the uncontrolled and persistent leakiness. The designed NPs can penetrate endothelial layers, expedite cell layer recovery, curtail tumor metastasis, and facilitate efficient cancer therapy.