Engineering Asymmetry: Geometric Design of Nanoscale Lipid Vesicles for Uptake-Optimized Drug Delivery

Abstract

It is often the case that therapeutics needed to treat particular diseases or ailments cannot be administered directly into the bloodstream or digestive system. Due to problems like toxicity in non-targeted environments or requirements for higher uptake by target cells, they often need to be transported by drug delivery vehicles. Today, a broad range of such vehicles are used, including Lipid NanoParticles (LNPs) and Viral Vectors, but they all face significant shortcomings (in this case, limited parameter space for packaging only negatively charged molecules, and size constraint of packages respectively). We explore a new type of drug delivery system, namely nanoscale bi-leaflet lipid vesicles, which have shown promise in encapsulating a large set of drugs without size or charge constraints. The biggest challenge currently facing lipid vesicles is limited cellular uptake, which we explore in this thesis through a geometric and symmetric lens. We show that asymmetry between the inner and outer leaflet of the vesicles enhances uptake by up to 9-fold in some cases, while showing that higher magnitudes of zeta potential and greater membrane fluidity enhance uptake as well. We also relate these empirical findings to geometric theory to synthesize our learnings and move toward an optimization model to maximize vesicle uptake by cells.This research hopes to contribute to forming more efficient, universal drug carriers and make it possible to transport therapeutics never delivered before, including the CRISPR Cas-9 gene-editing protein among other large, complex proteins and drugs.