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Lin, Y.* ; Wilk, U.* ; Pöhmerer, J.* ; Hörterer, E.* ; Höhn, M.* ; Luo, X.* ; Mai, H. ; Wagner, E.* ; Lächelt, U.*

Folate receptor-mediated delivery of Cas9 RNP for enhanced immune checkpoint disruption in cancer cells.

Small 19:e2205318 (2022)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system offers great opportunities for the treatment of numerous diseases by precise modification of the genome. The functional unit of the system is represented by Cas9/sgRNA ribonucleoproteins (RNP), which mediate sequence-specific cleavage of DNA. For therapeutic applications, efficient and cell-specific transport into target cells is essential. Here, Cas9 RNP nanocarriers are described, which are based on lipid-modified oligoamino amides and folic acid (FolA)-PEG to realize receptor-mediated uptake and gene editing in cancer cells. In vitro studies confirm strongly enhanced potency of receptor-mediated delivery, and the nanocarriers enable efficient knockout of GFP and two immune checkpoint genes, PD-L1 and PVR, at low nanomolar concentrations. Compared with non-targeted nanoparticles, FolA-modified nanocarriers achieve substantially higher gene editing including dual PD-L1/PVR gene disruption after injection into CT26 tumors in vivo. In the syngeneic mouse model, dual disruption of PD-L1 and PVR leads to CD8+ T cell recruitment and distinct CT26 tumor growth inhibition, clearly superior to the individual knockouts alone. The reported Cas9 RNP nanocarriers represent a versatile platform for potent and receptor-specific gene editing. In addition, the study demonstrates a promising strategy for cancer immunotherapy by permanent and combined immune checkpoint disruption.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Cellular Delivery ; Clustered Regularly Interspaced Short Palindromic Repeats/ Clustered Regularly Interspaced Short Palindromic Repeats-associated Protein 9 ; Folate Receptors ; Gene Editing ; Nanocarriers; Gene; Protein; Polyplexes; Cd155; Stability; Complexes; Melanoma; Release; Pathway; Tigit
Sprache englisch
Veröffentlichungsjahr 2022
HGF-Berichtsjahr 2022
ISSN (print) / ISBN 1613-6810
e-ISSN 1613-6829
Zeitschrift Small
Quellenangaben Band: 19, Heft: 2, Seiten: , Artikelnummer: e2205318 Supplement: ,
Verlag Wiley
Verlagsort Postfach 101161, 69451 Weinheim, Germany
Begutachtungsstatus Peer reviewed
Institut(e) Institute for Tissue Engineering and Regenerative Medicine (ITERM)
POF Topic(s) 30205 - Bioengineering and Digital Health
Forschungsfeld(er) Enabling and Novel Technologies
PSP-Element(e) G-505800-001
Förderungen
Galenus Foundation (Vienna, Austria)
China Scholarship Council
German Research Foundation (DFG)
European Union
UPGRADE (Unlocking Precision Gene Therapy)
DOI 10.1002/smll.202205318
WOS ID 000888820800001
WOS ID WOS:000888820800001
Scopus ID 85146123729
PubMed ID 36399647
Erfassungsdatum 2022-12-10
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