Reactive oxygen species(ROS)-mediated M1 macrophage-dependent nanomedicine remodels inflammatory microenvironment for osteoarthritis recession  

作　　者：Chunchun Xue Jia Tian Zepeng Cui Yang Liu Dawei Sun Mengting Xiong Nanxing Yi Kaiqiang Wang Xiaofeng Li Yongjun Wang Hao Xu Weian Zhang Qianqian Liang 

机构地区：[1]Longhua Hospital,Shanghai University of Traditional Chinese Medicine,Shanghai,200032,China [2]Spine Institute,Shanghai University of Traditional Chinese Medicine,Shanghai,200032,China [3]Key Laboratory of Theory and Therapy of Muscles and Bones,Ministry of Education,Shanghai University of Traditional Chinese Medicine,Shanghai,201203,China [4]Shanghai Key Laboratory of Functional Materials Chemistry,School of Chemistry and Molecular Engineering,East China University of Science and Technology,Shanghai,200237,China [5]Shanghai Municipal Hospital of Traditional Chinese Medicine,Shanghai University of Traditional Chinese Medicine,Shanghai,200071,China

出　　处：《Bioactive Materials》2024年第3期545-561,共17页生物活性材料（英文）

基　　金：supported by the following grants:National Natural Science Foundation(no.81920108032,81873321,81930116,81973881,81804122 and 52333014);State Administration of Traditional Chinese Medicine-Young Qhuang Scholar,New interdisciplinary research Project of Shanghai Municipal Health Commission(no.2022JC005);Traditional Chinese Medicine Research Project Innovation Team Project of Shanghai Health Commission(no.2022CX001);Shanghai"Science and Technology Innovation Action Plan"medical innovation research project(no.21Y11921400);Shanghai Top Priority Research Center Construction Project(no.2022ZZ01009);Shanghai University of TCM Xinglin Scholars Project(no.TCM[2020]23);Shanghai University of TCM Excellent Talents Training Program(no.TCM[2020]10).

摘　　要：Osteoarthritis(OA)is a common chronic inflammatory disorder.Effective remodeling of inflammatory microenvironment in the joint is a promising strategy to prevent OA.However,current drugs remain unsatisfactory due to a lack of targeted and effective ways for relieving inflammatory conditions in OA joints.Bortezomib(BTZ),a proteasome inhibitor,could effectively inhibit proinflammatory cytokines but with poor accumulation in the inflammatory tissues.To overcome the shortcomings of BTZ delivery and to improve the efficacy of OA therapy,herein,we designed a novel nanomedicine(denoted as BTZ@PTK)by the co-assembly of BTZ and an amphiphilic copolymer(denoted as PTK)with ROS-cleaved thioketal(TK)linkages.The TK units in BTZ@PTK are first cleaved by the excessive ROS at OA sites,and then triggered the controlled release of BTZ,resulting in the accurate delivery and the inflammatory microenvironment remodeling.Accordingly,BTZ@PTK suppressed ROS generation and proinflammatory cytokines while promoting M1 macrophage apoptosis in lipopolysaccharide(LPS)-activated RAW264.7 macrophages or LPS/IFN-γ-treated primary macrophages,which leads to a better effect than BTZ.In OA mice,BTZ@PTK passively accumulates into inflamed joints to attenuate pain sensitivity and gait abnormality.Importantly,BTZ@PTK treatment successfully ameliorates synovitis with the reduction of synovial hyperplasia and synovitis scores by suppressing M1 macrophage polarization and promoting M1 macrophage apoptosis in the synovium,thereby delaying cartilage damage.Collectively,BTZ@PTK can effectively modulate inflammatory microenvironment for OA recession by activating M1 macrophage apoptosis and inhibiting M1macrophage-mediated inflammatory response.

关 键 词：Reactive oxygen species OSTEOARTHRITIS Inflammatory microenvironment Macrophages polarization Apoptosis 

分 类 号：R684.3[医药卫生—骨科学]