Profibrogenic macrophage-targeted delivery of mitochondrial protector via exosome formula for alleviating pulmonary fibrosis  

作　　者：Wei Zhang Zhuo Wan Di Qu Wenqi Sun Liang Zhang Yuan Liang Lei Pan Hua Jiang Zichen Ye Mengying Wei Lijun Yuan Guodong Yang Faguang Jin 

机构地区：[1]Department of Pulmonary and Critical Care Medicine,Tangdu Hospital,Fourth Military Medical University,Xi’an,Shaanxi,710038,China [2]Department of Hematology,Tangdu Hospital,Fourth Military Medical University,Xi’an,Shaanxi,710038,China [3]Department of Cardiology,Xijing Hospital,Fourth Military Medical University,Xi’an,Shaanxi,710032,China [4]Department of Clinical Pharmacy,General Hospital of Western Theater Command,Chengdu,Sichuan,610083,China [5]Department of Ultrasound Diagnostics,Tangdu Hospital,Fourth Military Medical University,Xi’an,Shaanxi,710038,China [6]Department of Health Service,Health Service Training Base,Fourth Military Medical University,Xi’an,Shaanxi,710032,China [7]State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers,Department of Biochemistry and Molecular Biology,Fourth Military Medical University,Xi’an,Shaanxi,710032,China

出　　处：《Bioactive Materials》2024年第2期488-501,共14页生物活性材料（英文）

基　　金：supported by the National Natural Science Foundation of China(Grant Nos.NSFC 81970076);Key R&D Program of Shaanxi Province,China(2022ZDLSF01-10)。

摘　　要：Pulmonary fibrosis(PF)is a devastating lung disease with limited treatment options.During this pathological process,the profibrogenic macrophage subpopulation plays a crucial role,making the characterization of this subpopulation fundamentally important.The present study revealed a positive correlation between pulmonary macrophages with higher mitochondrial mass(Mø^(mitohigh))and fibrosis.Among the Mø^(mitohigh)subpopulation of CD206^(+)M2,characterized by higher expression of dynamin 1-like(Drp1),as determined by flow cytometry and RNA-seq analysis,a therapeutic intervention was developed using an exosome-based formula composed of pathfinder and therapeutics.A pathfinder exosome called“exosome^(MMP19)(Exo^(MMP19))”,was constructed to display matrix metalloproteinase-19(^(MMP19))on the surface to locally break down the excessive extracellular matrix(ECM)in the fibrotic lung.A therapeutic exosome called“exosome therapeutics(Exo^(Tx))”,was engineered to display D-mannose on the surface while encapsulating siDrp1 inside.Prior delivery of Exo^(MMP19)degraded excessive ECM and thus paved the way for Exo^(Tx)to be delivered into Mø^(mitohigh),where Exo^(Tx)inhibited mitochondrial fission and alleviated PF.This study has not only identified Mø^(mitohigh)as profibrotic macrophages but it has also provided a potent strategy to reverse PF via a combination of formulated exosomes.

关 键 词：Pulmonary fibrosis MACROPHAGES Mitochondrial fission Drp1 EXOSOMES 

分 类 号：R318[医药卫生—生物医学工程]