Genetically engineered and enucleated human mesenchymal stromal cells for the targeted delivery of therapeutics to diseased tissue

Huawei Wang, Christina N. Alarcón, Bei Liu, Felicia Watson, Stephen Searles, Calvin K. Lee, Jeremy Keys, Willie Pi, Dale Allen, Jan Lammerding, Jack D. Bui, Richard L. Klemke*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

Targeting the delivery of therapeutics specifically to diseased tissue enhances their efficacy and decreases their side effects. Here we show that mesenchymal stromal cells with their nuclei removed by density-gradient centrifugation following the genetic modification of the cells for their display of chemoattractant receptors and endothelial-cell-binding molecules are effective vehicles for the targeted delivery of therapeutics. The enucleated cells neither proliferate nor permanently engraft in the host, yet retain the organelles for energy and protein production, undergo integrin-regulated adhesion to inflamed endothelial cells, and actively home to chemokine gradients established by diseased tissues. In mouse models of acute inflammation and of pancreatitis, systemically administered enucleated cells expressing two types of chemokine receptor and an endothelial adhesion molecule enhanced the delivery of an anti-inflammatory cytokine to diseased tissue (with respect to unmodified stromal cells and to exosomes derived from bone-marrow-derived stromal cells), attenuating inflammation and ameliorating disease pathology. Enucleated cells retain most of the cells’ functionality, yet acquire the cargo-carrying characteristics of cell-free delivery systems, and hence represent a versatile delivery vehicle and therapeutic system.

Original languageEnglish (US)
Pages (from-to)882-897
Number of pages16
JournalNature Biomedical Engineering
Volume6
Issue number7
DOIs
StatePublished - Jul 2022

ASJC Scopus subject areas

  • Bioengineering
  • Biotechnology
  • Biomedical Engineering
  • Medicine (miscellaneous)
  • Computer Science Applications

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