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Advanced peptide nanoparticles enable robust and efficient delivery of gene editors across cell types
Department of Laboratory Medicine, Unit for Biomolecular and Cellular Medicine, Karolinska Institutet, Stockholm, Sweden; Karolinska ATMP center, Karolinska Institutet, Karolinska University Hospital, SE-17176 Stockholm, Sweden.
Muscle Research Unit, Experimental and Clinical Research Center (ECRC), a joint cooperation between the Charité – Universitätsmedizin Berlin and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany; Department of Biology, Chemistry, and Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany.
Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Huddinge, Stockholm, Sweden, Huddinge.
Division of Chemical Biology, Department of Life Sciences, Chalmers University of Technology, Kemivägen 10, 412 96 Gothenburg, Sweden, Kemivägen 10.
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2025 (English)In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 386, article id 114038Article in journal (Refereed) Published
Abstract [en]

Efficient delivery of the CRISPR/Cas9 system and its larger derivatives, base editors, and prime editors remain a major challenge, particularly in tissue-specific stem cells and induced pluripotent stem cells (iPSCs). This study optimized a novel family of cell-penetrating peptides, hPep, to deliver gene-editing ribonucleoproteins. The hPep-based nanoparticles enable highly efficient and biocompatible delivery of Cre recombinase, Cas9, base-, and prime editors. Using base editors, robust and nearly complete genome editing was achieved in the human cells: HEK293T (96%), iPSCs (74%), and muscle stem cells (80%). This strategy opens promising avenues for ex vivo and, potentially, in vivo applications. Incorporating silica particles enhanced the system's versatility, facilitating cargo-agnostic delivery. Notably, the nanoparticles can be synthesized quickly on a benchtop and stored as lyophilized powder without compromising functionality. This represents an important advancement in the feasibility and scalability of gene-editing delivery technologies.

Place, publisher, year, edition, pages
Elsevier BV , 2025. Vol. 386, article id 114038
Keywords [en]
Base and primer editor, Cell-penetrating peptide (CPP), Diverse cells, including MuSC and iPSC, Gene editing, Protein delivery, Synthetic gene editor delivery
National Category
Cell and Molecular Biology Medical Biotechnology (Focus on Cell Biology, (incl. Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Molecular Biology
Identifiers
URN: urn:nbn:se:kth:diva-369060DOI: 10.1016/j.jconrel.2025.114038ISI: 001551073700001PubMedID: 40684990Scopus ID: 2-s2.0-105011371022OAI: oai:DiVA.org:kth-369060DiVA, id: diva2:1998741
Note

QC 20250917

Available from: 2025-09-17 Created: 2025-09-17 Last updated: 2025-11-03Bibliographically approved

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Birdsong, Björn K.

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Cell and Molecular BiologyMedical Biotechnology (Focus on Cell Biology, (incl. Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)Molecular Biology

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