Influence of structural variations in polysarcosine functionalized lipids on lipid nanoparticle-mediated mRNA delivery

Lipid nanoparticles (LNPs) have been demonstrated to be potent and well-tolerated vehicles for delivering mRNA in vaccination and therapeutics. However, the presence of anti-poly(ethylene glycol) (PEG) antibodies in the body resulted in the problems of hypersensitivity reaction, accelerated blood clearance and high systemic reactogenicity after repeated dosing of PEG lipid-contained LNPs, thus limiting the utility for in vivo messenger RNA (mRNA) delivery. Here, we synthesized well-defined polysarcosine functionalized lipids (pSar-lipids) with various hydrophobic tail lengths and molecular weights by the accelerated ring-opening polymerization of sarcosine N -carboxyanhydride (NCA). The obtained pSar-lipids were utilized as PEG lipid alternatives to explore structure–activity relationships of pSar-lipid-based LNPs. The results demonstrated that pSar-lipid-based LNPs by intravenous administration represented higher mRNA delivery efficiency in the liver and spleen with the increased hydrophobic tail length of pSar-lipids. Importantly, more significant preference for mRNA delivery into the liver was identified by increasing the molecular weight of pSar segments. As a result, this work elucidated the effect of structural variations in pSar-lipids on LNP-mediated in vivo mRNA delivery, providing clues to optimize pSar-lipids as potential alternatives to PEG lipids for developing next-generation of LNP delivery systems. Graphical