Highly compacted biodegradable DNA nanoparticles capable of overcoming the mucus barrier for inhaled lung gene therapy

Panagiotis Mastorakos, Adriana L.Da Silva, Jane Chisholm, Eric Song, Won Kyu Choi, Michael P. Boyle, Marcelo M. Morales, Justin Hanes, Jung Soo Suk

Research output: Contribution to journalArticlepeer-review

Abstract

Gene therapy has emerged as an alternative for the treatment of diseases refractory to conventional therapeutics. Synthetic nanoparticle-based gene delivery systems offer highly tunable platforms for the delivery of therapeutic genes. However, the inability to achieve sustained, high-level transgene expression in vivo presents a significant hurdle. The respiratory system, although readily accessible, remains a challenging target, as effective gene therapy mandates colloidal stability in physiological fluids and the ability to overcome biological barriers found in the lung. We formulated highly stable DNA nanoparticles based on state-of-the-art biodegradable polymers, poly(β-amino esters) (PBAEs), possessing a dense corona of polyethylene glycol. We found that these nanoparticles efficiently penetrated the nanoporous and highly adhesive human mucus gel layer that constitutes a primary barrier to reaching the underlying epithelium. We also discovered that these PBAE-based mucus-penetrating DNA nanoparticles (PBAE-MPPs) provided uniform and high-level transgene expression throughout the mouse lungs, superior to several gold standard gene delivery systems. PBAE-MPPs achieved robust transgene expression over at least 4 mo following a single administration, and their transfection efficiency was not attenuated by repeated administrations, underscoring their clinical relevance. Importantly, PBAE-MPPs demonstrated a favorable safety profile with no signs of toxicity following intratracheal administration.

Original languageEnglish (US)
Pages (from-to)8720-8725
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number28
DOIs
StatePublished - Jul 14 2015

Keywords

  • Biodegradable polymer
  • Lung gene therapy
  • Mucus-penetrating particles
  • Nanotechnology
  • Nonviral gene delivery

ASJC Scopus subject areas

  • General

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