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 biomimetic 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 nonspecific interactions between diffusing particles and gel matrix environments.
