ERI: The impact of ionizable lipid chemistry and targeting ligands on biological interactions of lipid nanoparticles

Rowan University, Glassboro NJ

Investigators

Abstract

Lipid nanoparticles are ultrasmall drug delivery platforms that can package therapeutics, making them safer and more efficacious than the free therapeutics. In this project, the research team aims to understand how the design of lipid nanoparticles impacts their ability to enable high levels of drug delivery to cells and tissues. Although researchers know that the design of lipid nanoparticles impacts their effectiveness, the precise mechanisms by which this occurs remains elusive. Here, the research team will take a fundamental and mechanistic approach to understand how the chemical structure of the lipids impacts how the nanoparticles interact with cells and tissues. This award will enable the inclusion of one graduate student and two undergraduate students on this research, providing exceptional research opportunities to Biomedical Engineering students at Rowan University. Further, the project will enable the recruitment of one student from Rowan College of South Jersey, the local community college, through a unique partnership. Ultimately, the successful completion of this work will allow drug delivery researchers to specifically design lipids for improved drug delivery for a wide range of biological applications. The goal of this project is to study structure-function relationships between ionizable lipid chemistry and the biological interactions of lipid nanoparticles. Lipid nanoparticles have emerged at the forefront of translational drug delivery due to their use in the Pfizer and Moderna COVID-19 vaccines. Lipid nanoparticles are comprised of ionizable lipids, cholesterol, phospholipids, and poly(ethylene) glycol complexed with therapeutic nucleic acids. Despite the recent clinical advancements of lipid nanoparticles, remarkably little is known about how their composition and physicochemical properties impact their interactions with biological systems. It has been established that ionizable lipid chemistry dictates how they interact with cells and tissues to drive drug delivery efficiency. However, there is a major gap in knowledge regarding the precise means by which ionizable lipid structure influences how lipid nanoparticles interact with cells and tissues. Here, the research team will take a fundamental and mechanistic approach to evaluate how lipid nanoparticle composition impacts biological interactions at the molecular, cellular, and tissue levels. The overarching hypothesis is that the degree of saturation, alkyl tail length, and tail branching of the ionizable lipids drives how lipid nanoparticles behave including stability, cell uptake, cytosolic delivery, and tissue specificity and penetration. The research objectives are to: (1) synthesize an array of new ionizable lipids and assess how ionizable lipid structure impacts lipid nanoparticle stability and protein corona formation, and (2) evaluate how ionizable lipid chemistry (branched/linear, degree of saturation, tail length) impacts delivery, uptake, endosomal escape, and tissue penetration. In addition to these research objectives, this project has several educational goals. This award will enable the inclusion of one graduate student and two undergraduate students on this research, providing exceptional research opportunities to Biomedical Engineering students at Rowan University. Further, this project will enable the recruitment of one student from Rowan College of South Jersey, the local community college, through a unique partnership. The work described herein has the potential to transform the way lipid nanoparticles are developed and tested preclinically by enhancing our understanding of how ionizable lipid chemistry impacts interactions in biological systems. Ultimately, this will enable the drug delivery community to engineer next-generation platforms created through an efficient and data-driven approach. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.