Application of Lipid Nanoparticle (LNP) Design and Optimization Concepts to the Emerging Field of Protein-Based Virus-Like Particles (VLPs)

Abstract

Lipid nanoparticles have emerged as the dominant delivery technology for genetic medicines, reaching global use and attention with the success of mRNA-based COVID vaccines. However, LNPs face notable challenges related to biodegradability, extrahepatic targeting, and immunogenicity. VLPs, a newer class of protein-based nanocarriers, present a compelling alternative with distinct advantages including inherent biodegradability due to non-synthetic components, cellular targeting capability by leveraging viral surface proteins, and reduced immunogenicity enabling repeat-dose therapeutics. This thesis systematically evaluates the applicability of LNP design and optimization concepts to VLPs to help explore parallels and potential divergences to investigate if VLPs should be considered the superior delivery technology. The concepts explored include mechanisms of nanoparticle formulation, cargo encapsulation, biodegradability, cellular uptake, endosomal escape, and immune system evasion. While significant design parallels exist, the primary challenge limiting VLPs is their slower manufacturing speed due to reliance on cellular expression systems. The conclusion of this document proposes a future usage of VLPs as a modular technology to help increase the speed of discovery and help bring VLPs into the mainstream.