biostudies-literatureHolick CTBMWKThüringer AufbaubankDeutsche ForschungsgemeinschaftBundesministerium für Wirtschaft und KlimaschutzBASE-Lipide2411354https://www.ebi.ac.uk/biostudies/studies/S-EPMC12019917biostudies-literatureUnknown21(16)Polyoxazolines have long been considered as promising alternatives to poly(ethylene glycol) (PEG) due to their comparable properties, in particular regarding their stealth effect toward the immune system. Lipid nanoparticles (LNPs), as utilized, e.g., in the COVID-19 vaccines, contain PEG-lipids. However, alternatives are required because of the "PEG dilemma" recognized by an increase in anti-PEG antibodies in the human population. In this study, poly(2-ethyl-2-oxazoline) (PEtOx)-based lipids with different degrees of polymerization are synthesized and subsequently used to formulate mRNA-loaded LNPs. The effect of polymer chain length on the size, immunoreaction, and transfection efficiency is investigated in detail. In addition, in-depth transfection studies are performed using super-resoSmall (Weinheim an der Bergstrasse, Germany)Poly(2-ethyl-2-oxazoline) (POx) as Poly(ethylene glycol) (PEG)-Lipid Substitute for Lipid Nanoparticle Formulations.PMC12019917TAB “Innovative Pharmapolymers” 2021FGI0005316213987IGF 01IF22462N16LP401003SFB 1278TAB "Innovative Pharmapolymers" 2021FGI0005Klein TMehnert CAdermann FNischang ISchubert USFranke CStreiber MSchubert SHarder LHolick CTTraeger AHoeppener SAnufriev IfalsePoly(2-ethyl-2-oxazoline) (POx) as Poly(ethylene glycol) (PEG)-Lipid Substitute for Lipid Nanoparticle Formulations.Polyoxazolines have long been considered as promising alternatives to poly(ethylene glycol) (PEG) due to their comparable properties, in particular regarding their stealth effect toward the immune system. Lipid nanoparticles (LNPs), as utilized, e.g., in the COVID-19 vaccines, contain PEG-lipids. However, alternatives are required because of the "PEG dilemma" recognized by an increase in anti-PEG antibodies in the human population. In this study, poly(2-ethyl-2-oxazoline) (PEtOx)-based lipids with different degrees of polymerization are synthesized and subsequently used to formulate mRNA-loaded LNPs. The effect of polymer chain length on the size, immunoreaction, and transfection efficiency is investigated in detail. In addition, in-depth transfection studies are performed using super-reso2025-01-01T00:00:00Z2025 Apr2026-06-01T14:44:46.267Z2026-04-08T13:21:37.393ZS-EPMC120199174010354310.1002/smll.202411354