Lung gene therapy with highly compacted DNA nanoparticles that overcome the mucus barrier

Jung Soo Suk, Anthony J. Kim, Kanika Trehan, Craig S. Schneider, Liudmila Cebotaru, Owen M. Woodward, Nicholas J. Boylan, Michael P. Boyle, Samuel K. Lai, William B. Guggino, Justin Hanes

Research output: Contribution to journalArticlepeer-review

121 Scopus citations


Inhaled gene carriers must penetrate the highly viscoelastic and adhesive mucus barrier in the airway in order to overcome rapid mucociliary clearance and reach the underlying epithelium; however, even the most widely used viral gene carriers are unable to efficiently do so. We developed two polymeric gene carriers that compact plasmid DNA into small and highly stable nanoparticles with dense polyethylene glycol (PEG) surface coatings. These highly compacted, densely PEG-coated DNA nanoparticles rapidly penetrate human cystic fibrosis (CF) mucus ex vivo and mouse airway mucus ex situ. Intranasal administration of the mucus penetrating DNA nanoparticles greatly enhanced particle distribution, retention and gene transfer in the mouse lung airways compared to conventional gene carriers. Successful delivery of a full-length plasmid encoding the cystic fibrosis transmembrane conductance regulator protein was achieved in the mouse lungs and airway cells, including a primary culture of mucus-covered human airway epithelium grown at air-liquid interface, without causing acute inflammation or toxicity. Highly compacted mucus penetrating DNA nanoparticles hold promise for lung gene therapy.

Original languageEnglish (US)
Pages (from-to)8-17
Number of pages10
JournalJournal of Controlled Release
Issue number1
StatePublished - Mar 28 2014


  • Airway gene therapy
  • DNA nanoparticle
  • Mucus barrier
  • Multiple particle tracking

ASJC Scopus subject areas

  • Pharmaceutical Science


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