Polysarcosine-Functionalized Lipid Nanoparticles for Therapeutic mRNA Delivery

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

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)10634-10645
Number of pages12
JournalACS Applied Nano Materials
Volume3
Issue number11
DOIs
StatePublished - Nov 25 2020

Keywords

  • drug delivery
  • gene delivery
  • lipid nanoparticles
  • LNPs
  • mRNA
  • polysarcosine
  • precision medicine
  • SAXS

ASJC Scopus subject areas

  • Materials Science(all)

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