A facile method to prepare non-cationic mRNA lipid-nanoparticles based on frame guided assembly strategy

In recent years, lipid nanoparticle (LNP)-formulated messenger RNA (mRNA) has become a promising tool in vaccine development and protein replacement therapy. However, the cationic or ionizable lipid components in the current LNPs also bring the concerns on toxicity and immunogenicity. In this study, we have developed a novel cationic lipid-independent strategy to prepare mRNA-LNPs through frame-guided assembly (FGA). A general mRNA compacting method has been demonstrated to fold long mRNA strands into compact mRNA particles, which was subsequently served as the amphiphilic frames to guide the assembly of phospholipid through hydrophobic interaction. We have also demonstrated high mRNA encapsulation efficiency, good stability and intracellular delivery capability of our mRNA-LNPs, which is expected as a promising tool in mRNA therapeutics and vaccines.