Inhaled siRNA nanoparticles targeting IL11 inhibit lung fibrosis and improve pulmonary function post-bleomycin challenge

被引：107

作者：

Bai, Xin ^{[1
,2
]}

Zhao, Guolin ^{[1
,2
]}

Chen, Qijing ^{[1
,2
]}

Li, Zhongyu ^{[3
]}

Gao, Mingzhu ^{[1
,2
]}

Ho, William ^{[3
]}

Xu, Xiaoyang ^{[3
,4
]}

Zhang, Xue-Qing ^{[1
,2
]}

机构：

[1] Shanghai Jiao Tong Univ, Engn Res Ctr Cell & Therapeut Antibody, Minist Educ, 800 Dongchuan Rd, Shanghai 200240, Peoples R China

[2] Shanghai Jiao Tong Univ, Sch Pharm, 800 Dongchuan Rd, Shanghai 200240, Peoples R China

[3] New Jersey Inst Technol, Dept Chem & Mat Engn, Newark, NJ 07102 USA

[4] New Jersey Inst Technol, Dept Biomed Engn, Newark, NJ 07102 USA

来源：

SCIENCE ADVANCES | 2022年 / 8卷 / 25期

基金：

美国国家科学基金会;

关键词：

GROWTH-FACTOR-BETA; MOLECULAR-MECHANISMS; REPAIR MECHANISMS; ACTIVATION; EXPRESSION; DELIVERY; INFLAMMATION; MODEL; GENE;

D O I：

10.1126/sciadv.abn7162

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Interleukin-11 (IL-11) is a profibrotic cytokine essential for the differentiation of fibroblasts into collagen-secreting, actin alpha 2, smooth muscle-positive (ACTA2(+)) myofibroblasts, driving processes underlying the pathogenesis of idiopathic pulmonary fibrosis (IPF). Here, we developed an inhalable and mucus-penetrative nanoparticle (NP) system incorporating siRNA against IL11 (silL11@PPGC NPs) and investigated therapeutic potential for the treatment of IPF. NPs are formulated through self-assembly of a biodegradable PLGA-PEG diblock copolymer and a self-created cationic lipid-like molecule GO-C14 to enable efficient transmucosal delivery of silL11. Noninvasive aerosol inhalation hindered fibroblast differentiation and reduced ECM deposition via inhibition of ERK and SMAD2. Furthermore, silL11@PPGC NPs significantly diminished fibrosis development and improved pulmonary function in a mouse model of bleomycin-induced pulmonary fibrosis without inducing systemic toxicity. This work presents a versatile NP platform for the locally inhaled delivery of siRNA therapeutics and exhibits promising clinical potential in the treatment of numerous respiratory diseases, including IPF.

引用

页数：18

共 58 条

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