Phase-Separated Liposomes Hijack Endogenous Lipoprotein Transport and Metabolism Pathways to Target Subsets of Endothelial Cells In Vivo.

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.

Heparin length in the coating of extremely small iron oxide nanoparticles regulates in vivo theranostic applications.

The positive contrast of extremely small iron oxide nanoparticles (ESIONP) in magnetic resonance imaging (MRI) rejuvenates this class of metal nanoparticles (NP).Yet, the current synthesis often lacks the possibility of adjusting the core size (while it is a key element for ESIONP-based MRI contrast behaviour), and also involved multiple complex steps before obtaining a ready-to-use probe for medical applications. In this study, we faced these challenges by applying heparin oligosaccharides (HO) of different lengths as coatings for the preparation of HEP-ESIONP with a one-pot microwave method. We demonstrated that the HO length could control the core size during the synthesis to achieve optimal positive MRI contrast, and that HEP-ESIONP were endowed directly with anticoagulant properties and/or a specific antitumor activity, according to the HO used. Relevantly, positron emission tomography (PET)-based in vivo biodistribution study conducted with 68Ga core-doped HEP-ESIONP analogues revealed significant changes in the probe behaviours, the shortening of HO promoting a shift from hepatic to renal clearance. The different conformations of HO coatings and a thorough in vitro characterisation of the probes' protein coronas provided insight into this crucial impact of HO length on opsonization-mediated immune response and elimination. Overall, we were able to identify a precise HO length to get an ESIONP probe showing prolonged vascular lifetime and moderate accumulation in a tumor xenograft, balanced with a low uptake by non-specific organs and favourable urinary clearance. This probe met all prerequisites for advanced theranostic medical applications with a dual MRI/PET hot spot capability and potential antitumor activity.