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

Abstract

AbstractPoly(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.