Hydrogels dehydrate liposomes: the structural fate of lipid nanoparticles in the extracellular matrix

Drug-loaded liposomes are the most successful nanomedicine to date, with multiple FDA-approved systems for a myriad of diseases. While liposome circulation time in blood and retention in tissues have been studied in detail, the structural fate of liposomes—and nanoparticles in general—in the body has not been extensively investigated. This presentation explores the structural fate of liposomes in a synthetic hydrogel system with the aim of understanding the possible restructuring effects that liposomes experience in the natural extracellular matrix. Small angle X-ray scattering, confocal microscopy, and cryogenic transmission electron microscopy data demonstrate that poly(ethylene glycol) (PEG), gelatin, and alginate hydrogels cause 200-nm liposomes of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) to transform into micrometer-sized aggregates. These aggregates are composed of multilamellar vesicles around 100 nm in diameter with a mean interlamellar separation of 5.5 nm. Protecting the liposomes with a corona of PEG damps this restructuring effect, making the multilamellar vesicles formed less stable. We attribute this unilamellar to multilamellar transition to an osmotic driving force from the hydrogel environment.