1. Phase-Separated Liposomes Hijack Endogenous Lipoprotein Transport and Metabolism Pathways to Target Subsets of Endothelial Cells In Vivo
- Author
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Arias-Alpizar, Gabriela, Papadopoulou, Panagiota, Rios, Xabier, Pulagam, Krishna Reddy, Moradi, Mohammad Amin, Pattipeiluhu, Roy, Bussmann, Jeroen, Sommerdijk, Nico, Llop, Jordi, Kros, Alexander, Campbell, Frederick, Arias-Alpizar, Gabriela, Papadopoulou, Panagiota, Rios, Xabier, Pulagam, Krishna Reddy, Moradi, Mohammad Amin, Pattipeiluhu, Roy, Bussmann, Jeroen, Sommerdijk, Nico, Llop, Jordi, Kros, Alexander, and Campbell, Frederick
- Abstract
Plasma lipid transport and metabolism are essential to ensure correct cellular function throughout the body. Dynamically regulated in time and space, the well-characterized mechanisms underpinning plasma lipid transport and metabolism offers an enticing, but as yet underexplored, rationale to design synthetic lipid nanoparticles with inherent cell/tissue selectivity. Herein, a systemically administered liposome formulation, composed of just two lipids, that is capable of hijacking a triglyceride lipase-mediated lipid transport pathway resulting in liposome recognition and uptake within specific endothelial cell subsets is described. In the absence of targeting ligands, liposome-lipase interactions are mediated by a unique, phase-separated (“parachute”) liposome morphology. Within the embryonic zebrafish, selective liposome accumulation is observed at the developing blood-brain barrier. In mice, extensive liposome accumulation within the liver and spleen – which is reduced, but not eliminated, following small molecule lipase inhibition – supports a role for endothelial lipase but highlights these liposomes are also subject to significant “off-target” by reticuloendothelial system organs. Overall, these compositionally simplistic liposomes offer new insights into the discovery and design of lipid-based nanoparticles that can exploit endogenous lipid transport and metabolism pathways to achieve cell selective targeting in vivo.
- Published
- 2023