The protein corona hampers the transcytosis of transferrin-modified nanoparticles through blood–brain barrier and attenuates their targeting ability to brain tumor

• Published in: Biomaterials 2021-07, Vol.274, p.120888-120888, Article 120888
• Main Authors: Xiao, Wei, Wang, Yazhen, Zhang, Huilin, Liu, Yuwei, Xie, Rou, He, Xueqin, Zhou, Yang, Liang, Luqing, Gao, Huile
• Format: Article
• Language: English
• Subjects: Blood–brain barrier; Lysosomal escape; Protein corona; Targeting ability; Transcytosis
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2021.120888

The modification of targeting ligands on nanoparticles (NPs) is anticipated to enhance the delivery of therapeutics to diseased tissues. However, once exposed to the blood stream, NPs can immediately adsorb proteins to form the “protein corona,” which may greatly hinder the targeting ligand from binding to its receptor. For brain-targeting delivery, nanotherapeutics must traverse the blood–brain barrier (BBB) to enter the brain parenchyma and then target the diseased cells. However, it remains elusive whether, apart from receptor recognition, the protein corona can affect other processes involved in BBB transcytosis, such as endocytosis, intracellular trafficking, and exocytosis. Furthermore, the targeting ability of NPs toward diseased cells after transcytosis remains unclear. Herein, transferrin (Tf), a brain-targeting ligand, was coupled to NPs to evaluate BBB transcytosis and brain tumor targeting ability. Different impacts of the in vitro and in vivo protein corona on receptor targeting, lysosomal escape, and BBB transcytosis were found. The in vitro protein corona abolished the Tf-mediated effects of the abovementioned processes, whereas the in vivo protein corona attenuated these effects. After crossing the BBB, Tf retained its targeting specificity towards brain tumor cells. Together, these results revealed that several bound apolipoproteins, especially apolipoprotein A-I, may help NPs traverse the BBB, thereby providing novel insights into the development of brain-targeted delivery. [Display omitted]