Nanoparticle interactions with biological systems are intricate processes influenced by various factors, among which the formation of a protein corona plays a pivotal role. This research investigates a novel aspect of nano protein corona-cell interactions, focusing on the impact of the protein corona on the recovery of disrupted tight junctions in endothelial cells. We demonstrate that nanoparticle shape may not play a significant role in protein corona composition but the protein corona on the star nanoparticles induces the aggregates of ZO-1, which is quite important for the barriers’ integrity. Our research emphasizes the APOA1 pre-coating on the nanoparticles reduce a ZO-1 expression of endothelial cells offering a promising strategy for overcoming the bio barriers. These findings contribute to our understanding of the interplay between nanoparticles, protein corona, and endothelial cell junctions, offering insights for developing innovative therapeutic approaches targeting blood-brain barrier integrity. Our study holds promise for the future of nanomedicine. Understanding the interplay between nanoparticles, protein corona, and tight junction dynamics holds promise for advancing our knowledge of the nano drug delivery systems and developing strategies to mitigate potential adverse effects.