Biophysical approach for precision membrane engineering of lipid nanoparticle systems

Abstract

Multivalent ligand-receptor interactions involving soft-matter, membrane-enveloped biological and biomimetic nanoparticles (e.g., virus particles, exosomes, vesicles, lipid nanoparticles) at cellular membrane interfaces are critical to a wide range of biological functions and pathologies. This class of multivalent interactions has been widely explored by biological and biophysical measurement approaches but it has proven analytically challenging to track corresponding multivalency-related nanoparticle shape deformation processes due to limitations in conventional measurement approaches. Such deformation processes are biologically important and influenced by a balance between the multivalent binding interaction energy and membrane bending energy of soft-matter nanoparticles. From an engineering perspective, developing measurement approaches to characterize multivalency-induced nanoparticle shape deformation at lipid membrane interfaces can help to provide a biophysical understanding about how various design parameters affect the membrane nanomechanical properties of nanoparticles. As a model experimental system to characterize soft-matter nanoparticle-membrane interactions, this thesis presents a localized surface plasmon resonance (LSPR)-based measurement platform to characterize the binding interaction of ligand-modified lipid vesicles with a receptor-functionalized supported lipid bilayer (SLB) platform and to obtain nanomechanical insights into multivalency-induced vesicle shape deformation processes based on a combination of experiment and theory. Within this scope, analytical models of the LSPR-related physics and multivalent ligand-receptor complex dynamics were developed in order to quantify structural and energetic aspects of vesicle deformation. By utilizing this measurement approach and corresponding analytical models, it was possible to elucidate how key parameters like receptor and ligand densities, vesicle size, cholesterol fraction in vesicles, and solution pH affect multivalency-induced vesicle attachment and shape deformation processes. This study discusses the results in terms of the analytical merits of the LSPR technique to track nanoparticle shape deformation at lipid membrane interfaces compared to other measurement options as well as insights into how multivalent interactions affect the nanomechanical properties of lipid vesicles. The measurement approach and analytical framework developed in this thesis can be broadly extended to evaluate the multivalent interactions of different types of membrane-enveloped biological and biomimetic nanoparticles with engineered properties and also to demonstrate the utility of membrane biophysics approaches to study interfacial phenomena related to nanoparticle-membrane interactions in general.Doctor of Philosoph