Advanced peptide nanoparticles enable robust and efficient delivery of gene editors across cell types

Oskar Gustafsson; Supriya Krishna; Sophia Borate; Marziyeh Ghaeidamini; Xiuming Liang; Osama Saher; Raul Cuellar; Björn K Birdsong; Samantha Roudi; H Yesid Estupiñán; Evren Alici; C I Edvard Smith; Elin K Esbjörner; Simone Spuler; Olivier Gerrit de Jong; Helena Escobar; Joel Z Nordin; Samir E L Andaloussi

doi:10.1016/j.jconrel.2025.114038

Advanced peptide nanoparticles enable robust and efficient delivery of gene editors across cell types

Oskar Gustafsson^*
, Supriya Krishna
, Sophia Borate
, Marziyeh Ghaeidamini
, Xiuming Liang
, Osama Saher
, Raul Cuellar
, Björn K Birdsong
, Samantha Roudi
, H Yesid Estupiñán
, Evren Alici
, C I Edvard Smith
, Elin K Esbjörner
, Simone Spuler
, Olivier Gerrit de Jong
, Helena Escobar
, Joel Z Nordin^*
, Samir E L Andaloussi^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Article number	114038
Journal	Journal of controlled release : official journal of the Controlled Release Society
Volume	386
Early online date	18 Jul 2025
DOIs	https://doi.org/10.1016/j.jconrel.2025.114038
Publication status	Published - 10 Oct 2025

Bibliographical note

Publisher Copyright:
© 2025 The Authors

Funding

European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (DELIVER, grant agreement No 101001374) (S.E.A.)European Union's Horizon 2020 research and innovation programme (EXPERT, grant agreement No 825828) (S.E.A.)Swedish foundation of Strategic Research FormulaEx, SM19-0007 (S.E.A.)Cancerfonden project grant 21 1762 Pj 01H (S.E.A.)Swedish Research Council grant 4–258/2021 (S.E.A.)Swedish Research Council grant 2021-02407 (J.N.)CIMED junior investigator grant (J.N.)Helmholtz Validation fund 2021–2024 (SI.S.)Si.S. is an inventor on a technology for primary human muscle stem cell isolation and manufacturing (IP: (DE10 2014 216872), 2015 PCT (WO 2016/030371), granted in EU and US). Si.S. and H.E. are co-inventors on a pending patent application on gene editing of human muscle stem cells (European Patent 666 Office 21 160 696.7). Si.S. is co-founder of MyoPax GmbH and MyoPax Denmark ApS. European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (DELIVER, grant agreement No 101001374 ) (S.E.A.) European Union's Horizon 2020 research and innovation programme (EXPERT, grant agreement No 825828 ) (S.E.A.) Swedish Research Council grant 2021-02407 (J.N.) Swedish Research Council grant 4–258/2021 (S.E.A.)

Funders	Funder number
MyoPax GmbH
MyoPax
European Research Council
Horizon 2020 research and innovation programme
Swedish Research Council	2021-02407
European Commission	21 160 696.7
Vetenskapsrådet	DE10 2014 216872, WO 2016/030371
Horizon 2020 Framework Programme	101001374, 825828
Stiftelsen för Strategisk Forskning	4–258/2021

Keywords

Base and primer editor
Cell-penetrating peptide (CPP)
Diverse cells, including MuSC and iPSC
Gene editing
Protein delivery
Synthetic gene editor delivery

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10.1016/j.jconrel.2025.114038Licence: CC BY

Advanced peptide nanoparticles enable robust and efficient delivery of gene editors across cell typesFinal published version, 9.32 MBLicence: CC BY

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Gustafsson, O., Krishna, S., Borate, S., Ghaeidamini, M., Liang, X., Saher, O., Cuellar, R., Birdsong, B. K., Roudi, S., Estupiñán, H. Y., Alici, E., Smith, C. I. E., Esbjörner, E. K., Spuler, S., de Jong, O. G., Escobar, H., Nordin, J. Z., & Andaloussi, S. E. L. (2025). Advanced peptide nanoparticles enable robust and efficient delivery of gene editors across cell types. Journal of controlled release : official journal of the Controlled Release Society, 386, Article 114038. https://doi.org/10.1016/j.jconrel.2025.114038

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abstract = "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.",

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note = "Publisher Copyright: {\textcopyright} 2025 The Authors",

year = "2025",

month = oct,

day = "10",

doi = "10.1016/j.jconrel.2025.114038",

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Gustafsson, O, Krishna, S, Borate, S, Ghaeidamini, M, Liang, X, Saher, O, Cuellar, R, Birdsong, BK, Roudi, S, Estupiñán, HY, Alici, E, Smith, CIE, Esbjörner, EK, Spuler, S, de Jong, OG, Escobar, H, Nordin, JZ & Andaloussi, SEL 2025, 'Advanced peptide nanoparticles enable robust and efficient delivery of gene editors across cell types', Journal of controlled release : official journal of the Controlled Release Society, vol. 386, 114038. https://doi.org/10.1016/j.jconrel.2025.114038

TY - JOUR

T1 - Advanced peptide nanoparticles enable robust and efficient delivery of gene editors across cell types

AU - Gustafsson, Oskar

AU - Krishna, Supriya

AU - Borate, Sophia

AU - Ghaeidamini, Marziyeh

AU - Liang, Xiuming

AU - Saher, Osama

AU - Cuellar, Raul

AU - Birdsong, Björn K

AU - Roudi, Samantha

AU - Estupiñán, H Yesid

AU - Alici, Evren

AU - Smith, C I Edvard

AU - Esbjörner, Elin K

AU - Spuler, Simone

AU - de Jong, Olivier Gerrit

AU - Escobar, Helena

AU - Nordin, Joel Z

AU - Andaloussi, Samir E L

PY - 2025/10/10

Y1 - 2025/10/10

N2 - 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.

AB - 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.

KW - Base and primer editor

KW - Cell-penetrating peptide (CPP)

KW - Diverse cells, including MuSC and iPSC

KW - Gene editing

KW - Protein delivery

KW - Synthetic gene editor delivery

UR - https://www.scopus.com/pages/publications/105011371022

U2 - 10.1016/j.jconrel.2025.114038

DO - 10.1016/j.jconrel.2025.114038

M3 - Article

C2 - 40684990

SN - 0168-3659

VL - 386

JO - Journal of controlled release : official journal of the Controlled Release Society

JF - Journal of controlled release : official journal of the Controlled Release Society

M1 - 114038

ER -

Advanced peptide nanoparticles enable robust and efficient delivery of gene editors across cell types

Abstract

Bibliographical note

Funding

Keywords

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