PEG-free Lipid Nanoparticles for mRNA Delivery: Superhydrophilic Sulfoxide Polymer Coatings.

Lipid nanoparticles (LNPs) are the most widely applied nanocarriers for mRNA delivery in clinical use. However, the limited stability and increasingly recognized immunogenicity of PEG-based LNP formulations are potential impediments to the more widespread development of mRNA therapeutics. To address shortcomings in current LNP polymer coatings, we have developed a polymer-lipid conjugate based on the low-fouling sulfoxide polymer poly(2-(methylsulfinyl)ethyl acrylate) (PMSEA). The results show that LNPs formed from the PMSEA-DSPE conjugates with optimized polymer chain length have excellent stability, highly effective shielding, and low immunogenicity, favorable properties for PMSEA-DSPE to be incorporated as a component of mRNA nanocarriers. mRNA-LNP formulations were prepared with PMSEA-DSPE as an alternative to the PEGylated formulations. The stability, in vitro behavior, and transfection efficiency of the mRNA nanocarriers were evaluated, with PMSEA providing superior transfection efficiency compared with the PEG equivalents. This work demonstrates the potential of PMSEA mRNA-LNPs for further development as therapeutic delivery vehicles.