Substituting Poly(ethylene glycol) Lipids with Poly(2-ethyl-2-oxazoline) Lipids Improves Lipid Nanoparticle Repeat Dosing

Poly(ethylene glycol) (PEG)-lipids are used in Food-and-Drug-Administration-approved lipid nanoparticle (LNP)-RNA drugs, which are safe and effective. However, it is reported that PEG-lipids may also contribute to accelerated blood clearance and rare cases of hypersensitivity; this highlights the utility of exploring PEG-lipid alternatives. Here, it is shown that LNPs containing poly(2-ethyl-2-oxazoline) (PEOZ)-lipids can deliver messenger RNA (mRNA) to multiple cell types in mice inside and outside the liver. In addition, it is reported that LNPs formulated with PEOZ-lipids show reduced clearance from the bloodstream and lower levels of antistealth lipid immunoglobulin Ms than LNPs formulated with PEG-lipids. These data justify further exploration of PEOZ-lipids as alternatives to PEG-lipids in LNP-RNA formulations. Poly(ethylene glycol) (PEG) lipids are used in clinical lipid nanoparticles (LNPs), but are linked to adverse immune reactions. By substituting PEG in LNPs with poly(2-ethyl-2-oxazoline), it is shown that messenger RNA (mRNA) can be delivered to multiple cell types in mice with less drug clearance after multiple doses. image