Engineering of extracellular vesicles for efficient intracellular delivery of multimodal therapeutics including genome editors
Artikel i vetenskaplig tidskrift, 2025

Intracellular delivery of protein and RNA therapeutics represents a major challenge. Here, we develop highly potent engineered extracellular vesicles (EVs) by incorporating bio-inspired attributes required for effective delivery. These comprise an engineered mini-intein protein with self-cleavage activity for active cargo loading and release, and fusogenic VSV-G protein for endosomal escape. Combining these components allows high efficiency recombination and genome editing in vitro following EV-mediated delivery of Cre recombinase and Cas9/sgRNA RNP cargoes, respectively. In vivo, infusion of a single dose Cre loaded EVs into the lateral ventricle in brain of Cre-LoxP R26-LSL-tdTomato reporter mice results in greater than 40% and 30% recombined cells in hippocampus and cortex respectively. In addition, we demonstrate therapeutic potential of this platform by showing inhibition of LPS-induced systemic inflammation via delivery of a super-repressor of NF-ĸB activity. Our data establish these engineered EVs as a platform for effective delivery of multimodal therapeutic cargoes, including for efficient genome editing.

Författare

Xiuming Liang

Karolinska Institutet

Karolinska universitetssjukhuset

Shandong University

Dhanu Gupta

Karolinska Institutet

University of Oxford

Junhua Xie

Flanders Interuniversity Institute for Biotechnology

Universiteit Gent

Elien Van Wonterghem

Universiteit Gent

Flanders Interuniversity Institute for Biotechnology

Lien Van Hoecke

Flanders Interuniversity Institute for Biotechnology

Universiteit Gent

Justin Hean

Evox Therapeutics Limited

Zheyu Niu

Shandong First Medical University

Karolinska Institutet

Marziyeh Ghaeidamini

Chalmers, Life sciences, Kemisk biologi

Oscar P.B. Wiklander

Karolinska Institutet

Karolinska universitetssjukhuset

Wenyi Zheng

Karolinska Institutet

Karolinska universitetssjukhuset

Rim Jawad Wiklander

Karolinska Institutet

Rui He

Karolinska Institutet

Doste R. Mamand

Karolinska Institutet

Karolinska universitetssjukhuset

Jeremy P. Bost

Karolinska Institutet

Guannan Zhou

Karolinska Institutet

Obstetrics & Gynecology Hospital of Fudan University

Houze Zhou

Karolinska Institutet

Karolinska universitetssjukhuset

Samantha Roudi

Karolinska Institutet

Karolinska universitetssjukhuset

H. Yesid Estupiñán

Karolinska universitetssjukhuset

Karolinska Institutet

Universidad Industrial de Santander

Julia Rädler

Karolinska Institutet

Karolinska universitetssjukhuset

Antje M. Zickler

Karolinska universitetssjukhuset

Karolinska Institutet

André Görgens

Karolinska universitetssjukhuset

Karolinska Institutet

Universitats Klinikum Essen und Medizinische Fakultat

Vicky W.Q. Hou

Karolinska universitetssjukhuset

Karolinska Institutet

Radka Slovak

Evox Therapeutics Limited

Daniel W. Hagey

Karolinska Institutet

Karolinska universitetssjukhuset

Olivier G. de Jong

Utrechts Instituut voor Farmaceutische Wetenschappen

Aileen Geobee Uy

Karolinska Institutet

Uppsala universitet

Yuanyuan Zong

Shandong First Medical University

Imre Mäger

Tartu Ülikool

Carla Martin Perez

University of Oxford

Thomas C. Roberts

University of Oxford

Dave Carter

Evox Therapeutics Limited

Pieter Vader

University Medical Center Utrecht

Elin Esbjörner Winters

Chalmers, Life sciences, Kemisk biologi

Antonin de Fougerolles

Evox Therapeutics Limited

Matthew J.A. Wood

University of Oxford

Roosmarijn E. Vandenbroucke

Universiteit Gent

Flanders Interuniversity Institute for Biotechnology

Joel Z. Nordin

Karolinska Institutet

Karolinska universitetssjukhuset

Samir El-Andaloussi

Karolinska Institutet

Karolinska universitetssjukhuset

Nature Communications

2041-1723 (ISSN) 20411723 (eISSN)

Vol. 16 1 4028

Ämneskategorier (SSIF 2025)

Molekylärbiologi

Cellbiologi

DOI

10.1038/s41467-025-59377-y

Mer information

Senast uppdaterat

2025-05-09