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Engineered Polymer-siRNA Polyplexes Provide Effective Treatment of Lung Inflammation

Authors
Jeon, TaewonLuther, David C.Goswami, RitabritaBell, CharlotteNagaraj, HariniCicek, Yagiz AnilHuang, RuiMas-Rosario, Javier A.Elia, James L.Im, JungkyunLee, Yi-WeiLiu, YuanchangScaletti, FedericaFarkas, Michelle E.Mager, JesseRotello, Vincent M.
Issue Date
Mar-2023
Publisher
American Chemical Society
Keywords
Anti-inflammatory; siRNA; polymer; polyplex; cytosolic delivery; lung inflammation
Citation
ACS Nano, v.17, no.5, pp 4315 - 4326
Pages
12
Journal Title
ACS Nano
Volume
17
Number
5
Start Page
4315
End Page
4326
URI
https://scholarworks.bwise.kr/sch/handle/2021.sw.sch/22444
DOI
10.1021/acsnano.2c08690
ISSN
1936-0851
1936-086X
Abstract
Uncontrolled inflammation is responsible for acute and chronic diseases in the lung. Regulating expression of pro-inflammatory genes in pulmonary tissue using small interfering RNA (siRNA) is a promising approach to combatting respiratory diseases. However, siRNA therapeutics are generally hindered at the cellular level by endosomal entrapment of delivered cargo and at the organismal level by inefficient localization in pulmonary tissue. Here we report efficient anti-inflammatory activity in vitro and in vivo using polyplexes of siRNA and an engineered cationic polymer (PONI-Guan). PONI-Guan/siRNA polyplexes efficiently deliver siRNA cargo to the cytosol for highly efficient gene knockdown. Significantly, these polyplexes exhibit inherent targeting to inflamed lung tissue following intravenous administration in vivo. This strategy achieved effective (>70%) knockdown of gene expression in vitro and efficient (>80%) silencing of TNF-alpha expression in lipopolysaccharide (LPS)-challenged mice using a low (0.28 mg/kg) siRNA dosage.
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