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

J Control Release. 2014 Mar 28;178:8-17. doi: 10.1016/j.jconrel.2014.01.007. Epub 2014 Jan 14.


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.

Keywords: Airway gene therapy; DNA nanoparticle; Mucus barrier; Multiple particle tracking.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intranasal
  • Adult
  • Animals
  • CHO Cells
  • Cricetulus
  • Cystic Fibrosis / metabolism
  • Cystic Fibrosis / therapy
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
  • DNA / administration & dosage*
  • DNA / chemistry
  • Esophagus / metabolism
  • Female
  • Gastric Mucosa / metabolism
  • Gene Transfer Techniques*
  • Genetic Therapy
  • Humans
  • Lung / metabolism*
  • Mice, Inbred BALB C
  • Mucus / metabolism*
  • Nanoparticles / administration & dosage*
  • Nanoparticles / chemistry
  • Polyethylene Glycols / chemistry
  • Polyethyleneimine / chemistry
  • Polylysine / chemistry
  • Young Adult


  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Polylysine
  • Polyethylene Glycols
  • Polyethyleneimine
  • DNA