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<p>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.</p>

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Engineering of extracellular vesicles for efficient intracellular delivery of multimodal therapeutics including genome editors

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年4月29日

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  • Xiuming Liang,
  • Dhanu Gupta,
  • Junhua Xie,
  • Elien Van Wonterghem,
  • Lien Van Hoecke,
  • Justin Hean,
  • Zheyu Niu,
  • Marziyeh Ghaeidamini,
  • Oscar P. B. Wiklander,
  • Wenyi Zheng,
  • Rim Jawad Wiklander,
  • Rui He,
  • Doste R. Mamand,
  • Jeremy Bost,
  • Guannan Zhou,
  • Houze Zhou,
  • Samantha Roudi,
  • H. Yesid Estupiñán,
  • Julia Rädler,
  • Antje M. Zickler,
  • André Görgens,
  • Vicky W. Q. Hou,
  • Radka Slovak,
  • Daniel W. Hagey,
  • Olivier G. de Jong,
  • Aileen Geobee Uy,
  • Yuanyuan Zong,
  • Imre Mäger,
  • Carla Martin Perez,
  • Thomas C. Roberts,
  • Dave Carter,
  • Pieter Vader,
  • Elin K. Esbjörner,
  • Antonin de Fougerolles,
  • Matthew J. A. Wood,
  • Roosmarijn E. Vandenbroucke,
  • Joel Z. Nordin,
  • Samir EL Andaloussi

摘要

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.