Biological and Medicinal Chemistry

Lipase-mediated selective hydrolysis of lipid droplets in phase separated-liposomes

Authors

Abstract

The membrane-protein interface in lipid nanoparticles (LNPs) is important for their in vivo behavior. Better understanding may assist to evolve current drug delivery methods to more precise, cell- or tissue-specific nanomedicine. Previously, we demonstrated how phase separation can drive liposomes to cell specific accumulation in vivo, through the selective recognition of phase-separated liposomes by triacylglycerol lipases (TGLs). This exemplified how liposome morphology can determine the preferential interaction of nanoparticles with biologically relevant proteins. Here, we investigate in detail the lipase-induced morphological changes of phase separated liposomes - which bear a lipid droplet in their bilayer - and unravel how lipase recognizes and binds to the particles at a molecular level. We find that phase separated liposomes undergo selective lipolytic degradation of their lipid droplet while overall nanoparticle integrity remains intact. Next, we combined MD simulations and in vitro experiments to identify the Tryptophan-rich loop of the lipase – a region which is involved endogenously in lipoprotein binding – as the region through which the enzyme binds to the particle. We demonstrate that this preferential binding is due to the lipid packing defects induced on the membrane by phase separation. These findings are a significant example of selective LNP – protein communication and interaction, aspects that may further the control of the in vivo behavior of lipid nanoparticles.

Version notes

Prof Nico Sommerdijk was added as an authour

Content

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Supplementary material

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Supporting information
Supporting information file
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Table of Content Figure
Table of Content Figure