Shaun Grumelot, Naseeha Mohammed, Ghafar Yerima, Jorge Colonrosado, Seyed Amirhossein Sadeghi, Fei Fang, Kylie Hilsen, Brooke Shango, Amir Ata Saei, Amanda M Murray, Michael J Mitchell, Babak Borhan, Liangliang Sun, Hojatollah Vali, Mohammad R K Mofrad, Kathryn A Whitehead, Morteza Mahmoudi
The protein corona influences the in vivo biodistribution of ionizable lipid nanoparticles (LNPs) in nucleic acid delivery, yet their structural architecture remains poorly defined. Using cryo-transmission electron microscopy, we visualized LNP-protein interactions in their native state. We show that, unlike the discrete "fuzzy" shells observed on hard nanoparticles, LNPs displayed no peripheral protein shell. Instead, controlled incubation and competitive "dual-particle" assays, supported by molecular dynamics simulations, indicate that LNP membranes undergo localized thickening and electron-dense remodeling consistent with lipoprotein integration rather than surface adsorption. Similar features were observed in extracellular vesicles, suggesting that this behavior is shared among lipid-based carriers, and proteomic analysis identified apolipoproteins as the dominant associated proteins. Together, these findings support a model in which the biological identity of LNPs arises through membrane remodeling rather than shell-like adsorption and provide a framework for the rational design of targeted nanomedicines.