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

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(ethylene glycol) methyl ether methacrylate) (POEGMA), POEGMA-methacrylic acid (POEGMA (-)), POEGMA-2-(dimethylamino)ethyl methacrylate (POEGMA (+)), poly(<i>N</i>,<i>N</i>-dimethylacrylamide) (PDMA), and poly(<i>N</i>-(2-hydroxypropyl) methacrylamide) (PHPMA). Our results demonstrated that all three POEGMA LNPs, especially POEGMA (+) LNPs, exhibited minimal ABC effect after two weekly doses; in contrast, PDMA LNPs demonstrated significantly lower clearance in the presence of anti-PEG antibodies. This study highlights the potential of PEG-free polymer-LNPs as promising mRNA carriers that avoid rapid clearance with repeated administration.