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Geilenkeuser, J. ; Armbrust, N. ; Steinmaßl, E. ; Du, S.W.* ; Schmidt, S. ; Binder, E.M.H. ; Li, Y. ; Warsing, N.W. ; Wendel, S.V. ; von der Linde, F. ; Schiele, E.M. ; Niu, X. ; Stroppel, L. ; Berezin, O. ; Santl, T. ; Orschmann, T. ; Nelson, K. ; Gruber, C. ; Palczewska, G.* ; Menezes, C.R.* ; Risaliti, E.* ; Engfer, Z.J.* ; Koleci, N.* ; Schmidts, A.* ; Geerlof, A. ; Palczewski, K.* ; Westmeyer, G.G. ; Truong, D.J.J.

Engineered nucleocytosolic vehicles for loading of programmable editors.

Cell 188:51 (2025)
Publ. Version/Full Text DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Advanced gene editing methods have accelerated biomedical discovery and hold great therapeutic promise, but safe and efficient delivery of gene editors remains challenging. In this study, we present a virus-like particle (VLP) system featuring nucleocytosolic shuttling vehicles that retrieve pre-assembled Cas-effectors via aptamer-tagged guide RNAs. This approach ensures preferential loading of fully assembled editor ribonucleoproteins (RNPs) and enhances the efficacy of prime editing, base editing, trans-activators, and nuclease activity coupled to homology-directed repair in multiple immortalized, primary, stem cell, and stem-cell-derived cell types. We also achieve additional protection of inherently unstable prime editing guide RNAs (pegRNAs) by shielding the 3'-exposed end with Csy4/Cas6f, further enhancing editing performance. Furthermore, we identify a minimal set of packaging and budding modules that can serve as a platform for bottom-up engineering of enveloped delivery vehicles. Notably, our system demonstrates superior per-VLP editing efficiency in primary T lymphocytes and two mouse models of inherited retinal disease, highlighting its therapeutic potential.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Vlps ; Base Editing ; Cell Therapy ; Gene Delivery ; Gene Therapy ; Genome Editing ; In Vivo Delivery ; Prime Editing ; Virus-like Particles; Genomic Dna; Target Base; Stem-cells; Protein; Rna; Domain
ISSN (print) / ISBN 0092-8674
e-ISSN 1097-4172
Journal Cell
Quellenangaben Volume: 188, Issue: 10, Pages: , Article Number: 51 Supplement: ,
Publisher Cell Press
Publishing Place Cambridge, Mass.
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Insitute of Synthetic Biomedicine (ISBM)
Institute of Developmental Genetics (IDG)
Institute of Structural Biology (STB)
Grants University of California, Irvine School of Medicine Dean's Office grant
Free State of Bavaria within the framework of the Excellence Strategy of the Federal Government
Lander through the ONE MUNICH project Munich Multiscale Biofabrication
European Research Council
European Innovation Council
National Institutes of Health (NIH)
Department of Ophthalmology, Gavin Herbert Eye Institute at the University of California, Irvine
Research to Prevent Blindness award
NIH
German Federal Ministry of Education and Research (BMBF)