The therapeutic use of RNA interference is limited by the inability of siRNA molecules to reach their site of action, the cytosol of target cells. Lipid nanoparticles, including liposomes, are commonly employed as siRNA carrier systems to overcome this hurdle, although their widespread use remains limited due to a lack of delivery efficiency. More recently, nature’s own carriers of RNA, extracellular vesicles (EVs), are increasingly being considered as alternative siRNA delivery vehicles due to their intrinsic properties. However, they are difficult to load with exogenous cargo.
Researchers at the University Medical Center Utrecht prepare and evaluate EV-liposome hybrid nanoparticles (hybrids) as an alternative delivery system combining properties of both liposomes and EVs. The show that hybrids are spherical particles encapsulating siRNA, contain EV-surface makers, and functionally deliver siRNA to different cell types. The functional behavior of hybrids, in terms of cellular uptake, toxicity, and gene-silencing efficacy, is altered as compared to liposomes and varies among recipient cell types. Moreover, hybrids produced with cardiac progenitor cell (CPC) derived-EVs retain functional properties attributed to CPC-EVs such as activation of endothelial signaling and migration. To conclude, hybrids combine benefits of both synthetic and biological drug delivery systems and might serve as future therapeutic carriers of siRNA.
Production of liposomes and hybrids
A) Schematic illustration of hybrid production via thin-film hydration and extrusion. B–D) Schematic illustration of liposomes and hybrids encapsulating a mixture of fluorescent and nonfluorescent siRNA. Hybrids are produced at different protein-to-lipid ratios (w/w): C) 1:100 and D) 1:50.