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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)

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	Open Access Gold (Paid Option)

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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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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords 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

ISSN (print) / ISBN 1613-6810

e-ISSN 1613-6829

Journal Small

Quellenangaben Volume: 19, Issue: 2, Article Number: e2205318

Publisher Wiley

Publishing Place Postfach 101161, 69451 Weinheim, Germany

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute for Tissue Engineering and Regenerative Medicine (ITERM)

Grants
Galenus Foundation (Vienna, Austria)
China Scholarship Council
German Research Foundation (DFG)
European Union
UPGRADE (Unlocking Precision Gene Therapy)