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

Abstract 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.