ROS-responsive liposomes as an inhaled drug delivery nanoplatform for idiopathic pulmonary fibrosis treatment via Nrf2 signaling

作者全名："Liu, Junzhao; Wu, Zuohong; Liu, Yadong; Zhan, Zhu; Yang, Liping; Wang, Can; Jiang, Qinqin; Ran, Haitao; Li, Pan; Wang, Zhigang"

作者地址："[Liu, Junzhao; Liu, Yadong; Zhan, Zhu; Wang, Can; Jiang, Qinqin; Ran, Haitao; Li, Pan; Wang, Zhigang] Chongqing Med Univ, Affiliated Hosp 2, Dept Ultrasound, Chongqing Key Lab Ultrasound Mol Imaging, Chongqing, Peoples R China; [Wu, Zuohong] Chongqing Tradit Chinese Med Hosp, Dept Resp & Crit Care Med, Chongqing, Peoples R China; [Yang, Liping] Chongqing Med Univ, Key Lab Lab Med Diagnost, Chinese Minist Educ, Chongqing, Peoples R China; [Ran, Haitao; Li, Pan; Wang, Zhigang] Chongqing Med Univ, Affiliated Hosp 2, Inst Ultrasound & Maging, Chongqing, Peoples R China"

通信作者："Wang, ZG (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Ultrasound, Chongqing Key Lab Ultrasound Mol Imaging, Chongqing, Peoples R China.; Wang, ZG (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Inst Ultrasound & Maging, Chongqing, Peoples R China."

来源：JOURNAL OF NANOBIOTECHNOLOGY

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:000791810500005

JCR分区：Q1

影响因子：10.2

年份：2022

卷号：20

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Idiopathic pulmonary fibrosis; ROS-responsive liposome; Inhaled drug delivery; Dimethyl fumarate; Nrf2

摘要："Background: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease with pathophysiological characteristics of transforming growth factor-beta (TGF-beta), and reactive oxygen species (ROS)-induced excessive fibroblast-to-myofibroblast transition and extracellular matrix deposition. Macrophages are closely involved in the development of fibrosis. Nuclear factor erythroid 2 related factor 2 (Nrf2) is a key molecule regulating ROS and TGF-beta expression. Therefore, Nrf2 signaling modulation might be a promising therapy for fibrosis. The inhalation-based drug delivery can reduce systemic side effects and improve therapeutic effects, and is currently receiving increasing attention, but direct inhaled drugs are easily cleared and difficult to exert their efficacy.Therefore, we aimed to design a ROS-responsive liposome for the Nrf2 agonist dimethyl fumarate (DMF) delivery in the fibrotic lung. Moreover, we explored its therapeutic effect on pulmonary fibrosis and macrophage activation. Results: We synthesized DMF-loaded ROS-responsive DSPE-TK-PEG@DMF liposomes (DTP@DMF NPs). DTP@DMF NPs had suitable size and negative zeta potential and excellent capability to rapidly release DMF in a high-ROS environment. We found that macrophage accumulation and polarization were closely related to fibrosis development, while DTP@DMF NPs could attenuate macrophage activity and fibrosis in mice. RAW264.7 and NIH-3T3 cells coculture revealed that DTP@DMF NPs could promote Nrf2 and downstream heme oxygenase-1 (HO-1) expression and suppress TGF-beta and ROS production in macrophages, thereby reducing fibroblast-to-myofibroblast transition and collagen production by NIH-3T3 cells. In vivo experiments confirmed the above findings. Compared with direct DMF instillation, DTP@DMF NPs treatment presented enhanced antifibrotic effect. DTP@DMF NPs also had a prolonged residence time in the lung as well as excellent biocompatibility. Conclusions: DTP@DMF NPs can reduce macrophage-mediated fibroblast-to-myofibroblast transition and extracellular matrix deposition to attenuate lung fibrosis by upregulating Nrf2 signaling. This ROS-responsive liposome is clinically promising as an ideal delivery system for inhaled drug delivery."

基金机构："National Natural Science Foundation of China [82172092]; Chongqing Natural Science Foundation [cstc2021jcyj-bshX0192, cstc2021jcyj-bshX0058]"

基金资助正文：This work was supported by National Natural Science Foundation of China (Grant No. 82172092) and the Chongqing Natural Science Foundation for postdoctoral (Grant No. cstc2021jcyj-bshX0192 and cstc2021jcyj-bshX0058).