A Two-Pronged Pulmonary Gene Delivery Strategy: A Surface-Modified Fullerene Nanoparticle and a Hypotonic Vehicle

Daiqin Chen, Shuai Liu, Dinghao Chen, Jinhao Liu, Jerry Wu, Han Wang, Yun Su, Gijung Kwak, Xinyuan Zuo, Divya Rao, Honggang Cui, Chunying Shu, Jung Soo Suk

Research output: Contribution to journalArticlepeer-review

Abstract

Inhaled gene therapy poses a unique potential of curing chronic lung diseases, which are currently managed primarily by symptomatic treatments. However, it has been challenging to achieve therapeutically relevant gene transfer efficacy in the lung due to the presence of numerous biological delivery barriers. Here, we introduce a simple approach that overcomes both extracellular and cellular barriers to enhance gene transfer efficacy in the lung in vivo. We endowed tetra(piperazino)fullerene epoxide (TPFE)-based nanoparticles with non-adhesive surface polyethylene glycol (PEG) coatings, thereby enabling the nanoparticles to cross the airway mucus gel layer and avoid phagocytic uptake by alveolar macrophages. In parallel, we utilized a hypotonic vehicle to facilitate endocytic uptake of the PEGylated nanoparticles by lung parenchymal cells via the osmotically driven regulatory volume decrease (RVD) mechanism. We demonstrate that this two-pronged delivery strategy provides safe, wide-spread and high-level transgene expression in the lungs of both healthy mice and mice with chronic lung diseases characterized by reinforced delivery barriers.

Original languageEnglish (US)
Pages (from-to)15225-15229
Number of pages5
JournalAngewandte Chemie - International Edition
Volume60
Issue number28
DOIs
StatePublished - Jul 5 2021

Keywords

  • RVD effect
  • fullerene
  • gene delivery
  • hypotonic vehicles
  • inhalation

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry

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