Holick Caroline T, Klein Tobias, Mehnert Charlotte, Adermann Franziska, Anufriev Ilya, Streiber Michael, Harder Lukas, Traeger Anja, Hoeppener Stephanie, Franke Christian, Nischang Ivo, Schubert Stephanie, Schubert Ulrich S
Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University, Jena, Germany, Humboldtstraße 10, 07743, Jena, Germany.
Jena Center for Soft Matter (JCSM), Friedrich Schiller University, Jena, Germany, Philosophenweg 7, 07743, Jena, Germany.
Small. 2025 Apr;21(16):e2411354. doi: 10.1002/smll.202411354. Epub 2025 Mar 19.
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-resolution microscopy (SRM) to investigate the uptake mechanism of PEtOx-based LNPs in comparison to PEG-LNPs. These combined approaches are utilized to identify the best performing LNP, being superior to the commercial PEG-lipid used in the Comirnaty formulation.
由于聚恶唑啉具有与聚乙二醇（PEG）相当的性能，特别是在对免疫系统的隐身效应方面，长期以来一直被视为聚乙二醇（PEG）的有前途的替代品。例如在新冠疫苗中使用的脂质纳米颗粒（LNPs）含有聚乙二醇脂质。然而，由于人群中抗聚乙二醇抗体的增加所认识到的“聚乙二醇困境”，需要替代品。在本研究中，合成了具有不同聚合度的基于聚（2-乙基-2-恶唑啉）（PEtOx）的脂质，随后用于制备负载mRNA的脂质纳米颗粒。详细研究了聚合物链长度对尺寸、免疫反应和转染效率的影响。此外，使用超分辨率显微镜（SRM）进行深入的转染研究，以研究基于PEtOx的脂质纳米颗粒与聚乙二醇脂质纳米颗粒相比的摄取机制。这些综合方法用于鉴定性能最佳的脂质纳米颗粒，其优于Comirnaty制剂中使用的商业聚乙二醇脂质。
