Phase-Separated Lipid-Based Nanoparticles: Selective Behavior At The Nano-Bio Interface.

The membrane-protein interface on lipid-based nanoparticles influences their in vivo behavior. Better understanding may evolve current drug delivery methods towards effective targeted nanomedicine. Previously, we demonstrated the cell-specific accumulation of a liposome formulation in vivo, through the selective recognition of lipid phase separation by triglyceride lipases. This exemplified how liposome morphology and composition can determine nanoparticle-protein interactions. Here, we investigate the lipase-induced compositional and morphological changes of phase-separated liposomes - which bear a lipid droplet in their bilayer - and unravel how lipases recognize and bind to the particles. We observe the selective lipolytic degradation of the phase-separated lipid droplet, while nanoparticle integrity remains intact. Next, we identify the Tryptophan-rich loop of the lipase - a region responsible for endogenous lipoprotein binding - as the region with which the enzymes bind to the particles. This preferential binding is due to lipid packing defects induced on the liposome surface by phase separation. In parallel, we build upon the existing knowledge that phase separation leads to in vivo selectivity, to generate phase-separated mRNA-LNPs that target cell subsets in zebrafish embryos, with subsequent mRNA delivery and protein expression. Together, these findings can expand our current knowledge on selective nanoparticle-protein communications and in vivo behavior, aspects that will assist to gain control of lipid-based nanoparticles. This article is protected by copyright. All rights reserved.