Authors
Michael Streiber, Caroline T Holick, Lucas Gath, Ekaterina Tsarenko, Vivien Bachmann, Stavroula Litsiou, Lukas Harder, Laura J Rosenberger, Aleksandar Rusevski, Julian Kimmig, Stephan Culemann, Christian Franke, Claudia Waskow, Stephanie Hoeppener, Stephanie Schubert, Matthias Bros, Oliver Werz, Ivo Nischang, Michael Bauer, Adrian T Press, Ulrich S Schubert, Anja Traeger
Published in
Angewandte Chemie (International ed. in English). Oct 27, 2026. Epub Oct 27, 2026.
Abstract
Efficient, biocompatible, and flexible application of CRISPR-Cas9 remains a major challenge in gene therapy. This study addresses a novel formulation method, focusing on organic solvent-free lipid nanoparticles for the efficient delivery of CRISPR-Cas9 components. Therefore, novel stealth lipids comprising the lipid anchor cholesterol hemisuccinate conjugated to poly(2-ethyl-2-oxazoline) (PEtOx) were synthesized and evaluated as a promising in vitro alternative to commercially available poly(ethylene glycol) (PEG)-based lipids. Our study identified PEtOx-lipids as markedly more biocompatible compared to PEG-based analogues (12-fold reduction in cytotoxicity; 99% reduced hemolytic effect) with high efficiency for mRNA gene delivery. We demonstrate successful CRISPR-Cas9 activity ex vivo and efficient uptake of PEtOx nanoparticles by macrophages in vivo (66.5% pos. F4/80+ macrophages). Our data demonstrate that PEtOx-based stealth lipids are a promising alternative to PEG. The resulting LNPs, optimized for fully aqueous manufacturing, address key limitations of current LNP systems, including immunogenicity and the reliance on ethanol-based production processes.
PMID:
42935313
Bibliographic data and abstract were imported from PubMed on 27 Oct 2026.
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