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

doi:10.1021/acsanm.0c01834

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 journal › Article › peer-review

114 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 language	English (US)
Pages (from-to)	10634-10645
Number of pages	12
Journal	ACS Applied Nano Materials
Volume	3
Issue number	11
DOIs	https://doi.org/10.1021/acsanm.0c01834
State	Published - Nov 25 2020

Keywords

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

ASJC Scopus subject areas

Materials Science(all)

Access to Document

10.1021/acsanm.0c01834

Cite this

@article{fc18905ff9ca4c3795dd379fdc12eb77,

title = "Polysarcosine-Functionalized Lipid Nanoparticles for Therapeutic mRNA Delivery",

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. ",

keywords = "LNPs, SAXS, drug delivery, gene delivery, lipid nanoparticles, mRNA, polysarcosine, precision medicine",

author = "Nogueira, {Sara S.} and Anne Schlegel and Konrad Maxeiner and Benjamin Weber and Matthias Barz and Schroer, {Martin A.} and Blanchet, {Clement E.} and Svergun, {Dmitri I.} and Srinivas Ramishetti and Dan Peer and Peter Langguth and Ugur Sahin and Heinrich Haas",

note = "Funding Information: U.S., P.L., and M.B. would like to acknowledge funding by the Deutsche Forschungsgemeinschaft (Collaborative Research Center 1066). A Lewis Trust grant was awarded to Dan Peer. We would like to thank to Janina Kuschmann for the support on physicochemical and in vitro analysis, all the animal groups for the support on the animal experiments, and finally the synthesis unit of BioNTech for the RNA synthesis. We also would like to thank Rachel Xerri for proofreading of the manuscript. We would like to thank Cristina Sala for creating the graphical abstract and the LNP cartoon. Publisher Copyright: {\textcopyright} 2020 American Chemical Society.",

year = "2020",

month = nov,

day = "25",

doi = "10.1021/acsanm.0c01834",

language = "English (US)",

volume = "3",

pages = "10634--10645",

journal = "ACS Applied Nano Materials",

issn = "2574-0970",

publisher = "American Chemical Society",

number = "11",

}

TY - JOUR

T1 - Polysarcosine-Functionalized Lipid Nanoparticles for Therapeutic mRNA Delivery

AU - Nogueira, Sara S.

AU - Schlegel, Anne

AU - Maxeiner, Konrad

AU - Weber, Benjamin

AU - Barz, Matthias

AU - Schroer, Martin A.

AU - Blanchet, Clement E.

AU - Svergun, Dmitri I.

AU - Ramishetti, Srinivas

AU - Peer, Dan

AU - Langguth, Peter

AU - Sahin, Ugur

AU - Haas, Heinrich

N1 - Funding Information: U.S., P.L., and M.B. would like to acknowledge funding by the Deutsche Forschungsgemeinschaft (Collaborative Research Center 1066). A Lewis Trust grant was awarded to Dan Peer. We would like to thank to Janina Kuschmann for the support on physicochemical and in vitro analysis, all the animal groups for the support on the animal experiments, and finally the synthesis unit of BioNTech for the RNA synthesis. We also would like to thank Rachel Xerri for proofreading of the manuscript. We would like to thank Cristina Sala for creating the graphical abstract and the LNP cartoon. Publisher Copyright: © 2020 American Chemical Society.

PY - 2020/11/25

Y1 - 2020/11/25

N2 - 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.

AB - 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.

KW - LNPs

KW - SAXS

KW - drug delivery

KW - gene delivery

KW - lipid nanoparticles

KW - mRNA

KW - polysarcosine

KW - precision medicine

UR - http://www.scopus.com/inward/record.url?scp=85095841396&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85095841396&partnerID=8YFLogxK

U2 - 10.1021/acsanm.0c01834

DO - 10.1021/acsanm.0c01834

M3 - Article

AN - SCOPUS:85095841396

SN - 2574-0970

VL - 3

SP - 10634

EP - 10645

JO - ACS Applied Nano Materials

JF - ACS Applied Nano Materials

IS - 11

ER -

Polysarcosine-Functionalized Lipid Nanoparticles for Therapeutic mRNA Delivery

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this