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 FDA-approved lipid nanoparticle (LNP)-RNA drugs, which are safe and effective. However, it has been 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 we show that LNPs containing poly(2-ethyl-2-oxazoline) (PEOZ)-lipids can deliver mRNA to multiple cell types in mice inside and outside the liver. In addition, we report that LNPs formulated with PEOZ-lipids show reduced clearance from the bloodstream and lower levels of anti-stealth lipid IgMs than LNPs formulated with PEG-lipids. These data justify further exploration of PEOZ-lipids as alternatives to PEG-lipids in LNP-RNA formulations. This article is protected by copyright. All rights reserved.