Polyglycerol‐Based Lipids: A Next‐Generation Alternative to PEG in Lipid Nanoparticles for Advanced Drug Delivery Systems

Polyethylene glycol (PEG) is widely used to provide a stealth effect in various therapeutic applications. However, an increased occurrence of anti-PEG antibodies in patients can lead to immunological side effects and accelerated blood clearance, reducing the efficiency of PEG-based delivery vectors. One of these PEG-containing vectors is lipid nanoparticles (LNPs), which effectively deliver nucleic acids. Their high potential for treating a great number of diseases in the future was already showcased in the mRNA vaccines developed during the COVID-19 pandemic. Thus, the aim of our study was to formulate LNP systems utilizing linear polyglycerol (lPG) as an alternative stealth polymer to avoid anti-PEG antibodies while enabling mRNA delivery. Our study showed that lPG-functionalized LNPs had negligible binding to IgG anti-PEG antibodies, while successfully delivering eGFP mRNA into HepG2 cells with comparable transfection efficiency as PEGylated LNPs.