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

Abstract

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