Polysarcosine-Functionalized Lipid Nanoparticles for Therapeutic mRNA Delivery
journal contributionposted on 16.10.2020, 14:32 by Sara S. Nogueira, Anne Schlegel, Konrad Maxeiner, Benjamin Weber, Matthias Barz, Martin A. Schroer, Clement E. Blanchet, Dmitri I. Svergun, Srinivas Ramishetti, Dan Peer, Peter Langguth, Ugur Sahin, Heinrich Haas
Polysarcosine (pSar) is a polypeptoid based on the endogenous amino acid sarcosine (N-methylated glycine), which has previously shown potent stealth properties. Here, lipid nanoparticles (LNPs) for therapeutic application of messenger RNA were assembled using pSarcosinylated lipids as a tool for particle engineering. Using pSar lipids with different polymeric chain lengths and molar fractions enabled the control of the physicochemical characteristics of the LNPs, such as particle size, morphology, and internal structure. In combination with a suited ionizable lipid, LNPs were assembled, which displayed high RNA transfection potency with an improved safety profile after intravenous injection. Notably, a higher protein secretion with a reduced immunostimulatory response was observed when compared to systems based on polyethylene glycol (PEG) lipids. pSarcosinylated nanocarriers showed a lower proinflammatory cytokine secretion and reduced complement activation compared to PEGylated LNPs. In summary, the described pSar-based LNPs enable safe and potent delivery of mRNA, thus signifying an excellent basis for the development of PEG-free RNA therapeutics.
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lipid nanoparticleschain lengthsstealth propertiesproinflammatory cytokine secretioncomplement activationparticle engineeringmolar fractionspSarcosinylated nanocarriersPEG-free RNA therapeuticsacid sarcosinePEGylated LNPsprotein secretionionizable lipidpSar-based LNPsTherapeutic mRNA Delivery PolysarcosineRNA transfection potencyparticle sizepSar lipidsmessenger RNApSarcosinylated lipidsPolysarcosine-Functionalized Lipid ...safety profileimmunostimulatory responsepolyethylene glycolphysicochemical characteristics