An insightful paper providing evidence that lipoproteins incorporate themselves into lipid nanoparticles (LNPs) rather than just adhering the surface as people previously thought. This may inform the design of better LNP delivery systems in the future.

Abstract. 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.