Unraveling Plasma Protein Corona by Ultrasonic Cavitation Augments Active-Transporting of Liposome in Solid Tumor.

Ligand/receptor-mediated targeted drug delivery has been widely recognized as a promising strategy for improving nanomedicines' clinical efficacy but was attenuated by the binding of plasma protein on the surface of nanoparticles to form protein corona. Here, we show that ultrasonic cavitation can be used to unravel surface plasma coronas on liposomal nanoparticles through ultrasound (US)-induced liposomal reassembly. To demonstrate the feasibility and effectiveness of the method, we developed transcytosis-targeting peptide decorated reconfigurable liposomes (LPGL) loaded with gemcitabine (GEM) and perfluoropentane (PFP) for cancer-targeted therapy. In the blood circulation, the targeting peptides were deactivated by plasma corona and lost their targeting capability. Once they reached tumor blood vessels, the US irradiation induced transformation of LPGL from nanodrops into microbubble via liquid-gas phase transition and decorticated surface corona by reassembly of the lipid membrane. The activated liposomes regained the capability to recognize the receptors on tumor neovascularization, initiated ligand/receptor-mediated transcytosis, achieved efficient tumor accumulation and penetration, and led to potent antitumor activity in multiple tumor models of patient-derived tumor xenograft. This study presents an effective strategy to tackle the fluid biological barriers of protein corona and develop transcytosis-targeting liposomes for active tumor transport and efficient cancer therapy. This article is protected by copyright. All rights reserved.