The COVID-19 pandemic demonstrated the importance of drug delivery. There, an mRNA was encapsulated inside a lipid-based container to protect it from degradation within the human body to engineer an efficient vaccine against COVID-19. However, vaccines are only one of the possible applications of drug delivery. If we could encapsulate and deliver any nucleic acid, protein or small molecule into drug delivery vehicles we could also design new treatment methods for gene and cancer therapy. Current strategies to encapsulate drugs rely on lipid nanoparticles, virus-like particles or liposomes. While lipid nanoparticles have proven extremely successful for the delivery of mRNA, the necessary charge-specific lipid-mRNA interaction prevents encapsulation of proteins or small molecules. Virus-like particles can encapsulate any cargo that fits into their shell. Their small size, however, prevents efficient encapsulation of large proteins, and their laborious preparation limits their use-cases for current delivery strategies. Liposomes are aqueous compartments surrounded by a lipid bilayer. They are easy to fabricate but can lack tunability and suffer low cellular uptake and encapsulation efficiencies compared to lipid nanoparticles and virus-like particles. If we could expand the scope for manipulating and tailoring lipid membrane properties of liposomes, we could engineer drug delivery vehicles that can encapsulate any cargo while also having a higher uptake by cells.

 

Here, we propose to engineer asymmetric polysaccharide-coated lipid vesicles to broaden the parameter space for engineering the mechanical and biochemical properties of lipid vesicles. We will use an inverted emulsion technique to form lipid vesicles with distinct leaflets, where each leaflet can be individually configured and modified. Additionally, we will functionalize the lipid vesicles with polysaccharides to enable cell-specific targeting. By tuning individual lipids on the inner and outer leaflet, this method will enable increased drug retention and encapsulation inside lipid vesicles. It will also lead to improved liposome uptake and transfection due to an unprecedented control over the vesicle properties. Additionally, polysaccharide modifications will provide the means for the targeted delivery to specific cell types via polysaccharide-specific recognition. This will reduce the cost and side effects compared to current drug delivery vehicles and might lead to a completely new generation of vaccine technology and disease treatment.

 

Our method is of significant commercial potential because it enables encapsulation of any cargo and is not limited to nucleic acids. It could also allow the targeting of organs beyond the liver, which makes it particularly interesting for cancer treatment, where the specific targeting of cancerous tissue will reduce side effects. The reduced cytotoxicity of asymmetric vesicles will also be important to maintain organ homeostasis during delivery.