Nonspecific membrane-matrix interactions influence diffusivity of lipid vesicles in hydrogels

Abstract

The diffusion of extracellular vesicles and liposomes in vivo is affected by different tissue environmental conditions and is of great interest in the development of liposome-based therapeutics and drug-delivery systems. Here, we use a bottom-up biomi-metic approach to better isolate and study steric and electrostatic interactions and their influence on the diffusivity of synthetic large unilamellar vesicles in hydrogel environments. Single-particle tracking of these extracellular vesicle-like particles in agarose hydrogels as an extracellular matrix model shows that membrane deformability and surface charge affect the hydrogel pore spaces that vesicles have access to, which determines overall diffusivity. Moreover, we show that passivation of vesicles with PEGylated lipids, as often used in drug delivery systems enhances diffusivity, but that this effect cannot be fully explained with electrostatic interactions alone. Finally, we compare our experimental findings with existing computational and theoretical work in the field to help explain the non-specific interactions between diffusing particles and gel matrix environments. Statement of SignificanceThe diffusion of nanoparticles in human tissues is dependent on interactions with the surrounding environment. This has wide implications for the development of nanoparticle-based therapeutics and drug delivery systems. Studying these interactions in human tissues and even in model hydrogels composed of reconstituted tissue components can be hampered by the many different complex interactions that can occur. By using a bio-inert hydrogel material like agarose, we remove the influence of specific biochemical interactions, allowing the study of how particle diffusion can be tuned with simple material properties like charge and rigidity. Taking advantage of these non-specific interactions, nanoparticles could one day be engineered to target specific organs by optimizing diffusion in certain tissue environments or retention and immobilization in others.