Influence of hydrophilic polymers on the accelerated blood clearance of mRNA lipid nanoparticles upon repeated administration

Abstract

mRNA lipid nanoparticles (LNPs) have emerged as a leading delivery system for mRNA-based vaccines and therapeutics. However, a significant limitation of this system is the presence of poly(ethylene) glycol (PEG). It is widely known that repeated doses of PEG-based therapeutics can induce an anti-PEG antibody response, leading to the accelerated blood clearance (ABC) of LNP therapeutics requiring frequent dosing, as anti-PEG antibodies have been found present in a large proportion of the population. To address this issue, we developed a mouse model for LNP clearance after a repeated dose. We then synthesised LNPs with the PEG component replaced by a library of hydrophilic polymers: poly(oligo..