Replacing poly(ethylene glycol) with RAFT lipopolymers in mRNA lipid nanoparticle systems for effective gene delivery

Lipid nanoparticles (LNPs) have emerged as promising carriers to efficiently transport mRNA into cells for protein translation, as seen with the mRNA vaccines used against COVID-19. However, they contain a widely used polymer - poly(ethylene glycol) (PEG) - which lacks the functionality to be easily modified (which could effectively control the physicochemical properties of the LNPs such as its charge), and is also known to be immunogenic. Thus, it is desirable to explore alternative polymers which can replace the PEG component in mRNA LNP vaccines and therapeutics, while still maintaining their efficacy. Herein, we employed reversible addition-fragmentation chain transfer (RAFT) polymerisation to synthesise five PEG-lipid alternatives that could stabilise LNPs encapsulating mRNA or pDNA molecules. Importantly, the resultant RAFT lipopolymer LNPs exhibit analogous or higher in vivo gene expression and antigen-specific antibody production compared to traditional PEG-based formulations. Our synthesis strategy which allows the introduction of positive charges along the lipopolymer backbone also significantly improved the in vivo gene expression. This work expands the potential of RAFT polymer-conjugated LNPs as promising mRNA carriers and offers an innovative strategy for the development of PEG-free mRNA vaccines and therapeutics.