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A Two‐Pronged Pulmonary Gene Delivery Strategy: A Surface‐Modified Fullerene Nanoparticle and a Hypotonic Vehicle
Author(s) -
Chen Daiqin,
Liu Shuai,
Chen Dinghao,
Liu Jinhao,
Wu Jerry,
Wang Han,
Su Yun,
Kwak Gijung,
Zuo Xinyuan,
Rao Divya,
Cui Honggang,
Shu Chunying,
Suk Jung Soo
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202101732
Subject(s) - gene delivery , genetic enhancement , lung , polyethylene glycol , peg ratio , transgene , in vivo , artificial lung , nanotechnology , microbiology and biotechnology , materials science , chemistry , medicine , gene , biology , biochemistry , neuroscience , finance , economics
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.