Bimetallic clusterzymes-loaded dendritic mesoporous silica particle regulate arthritis microenvironment via ROS scavenging and YAP1 stabilization  

作　　者：Yang Jin Chuan Hu Jiechao Xia Dingqi Xie Lin Ye Xinyi Ye Li Jiang Honghai Song Yutao Zhu Sicheng Jiang Weiqing Li Weiming Qi Yannan Yang Zhijun Hu 

机构地区：[1]Department of Orthopaedic Surgery,Key Laboratory of Musculoskeletal System Degeneration and Regeneration TranslationalResearch of Zhejiang Province,Sir Run Run Shaw Hospital,Medical College of Zhejiang University,Hangzhou,310016,China [2]Zhejiang University School of Medicine,Zhejiang University,Hangzhou,China [3]Department of Biochemistry and Molecular Biology,School of Basic Medical Sciences,Hangzhou Normal University,Hangzhou,China [4]Institute of Optoelectronics,Fudan University,Shanghai,200433,China [5]South Australian ImmunoGENomics Cancer Institute,Faculty of Health and Medical Sciences,The University of Adelaide,Adelaide,South Australia,5005,Australia [6]Zhejiang Center for Medical Device Evaluation,Zhejiang Medical Products Administration Hangzhou 310009,Zhejiang,China

出　　处：《Bioactive Materials》2024年第12期613-627,共15页生物活性材料（英文）

基　　金：supported by the Natural Science Foundation of Zhejiang Province of China(No.LY22H060003);The National Natural Science Foundation of China(82470903 to LJ);the Natural Science Foundation of Zhejiang Province(LY24C110001 to LJ).

摘　　要：Clusterzymes are synthetic enzymes exhibiting substantial catalytic activity and selectivity,which are uniquely driven by single-atom constructs.A dramatic increase in antioxidant capacity,158 times more than natural trolox,is noted when single-atom copper is incorporated into gold-based clusterzymes to form Au_(24)Cu_(1).Considering the inflammatory and mildly acidic microenvironment characteristic of osteoarthritis(OA),pH-dependent dendritic mesoporous silica nanoparticles(DMSNs)coupled with PEG have been employed as a delivery system for the spatial-temporal release of clusterzymes within active articular regions,thereby enhancing the duration of effectiveness.Nonetheless,achieving high therapeutic efficacy remains a significant challenge.Herein,we describe the construction of a Clusterzymes-DMSNs-PEG complex(CDP)which remarkably diminishes reactive oxygen species(ROS)and stabilizes the chondroprotective protein YAP by inhibiting the Hippo pathway.In the rabbit ACLT(anterior cruciate ligament transection)model,the CDP complex demonstrated inhibition of matrix metalloproteinase activity,preservation of type Ⅱ collagen and aggregation protein secretion,thus prolonging the clusterzymes’protective influence on joint cartilage structure.Our research underscores the efficacy of the CDP complex in ROS-scavenging,enabled by the release of clusterzymes in response to an inflammatory and slightly acidic environment,leading to the obstruction of the Hippo pathway and downstream NF-κB signaling pathway.This study illuminates the design,composition,and use of DMSNs and clusterzymes in biomedicine,thus charting a promising course for the development of novel therapeutic strategies in alleviating OA.

关 键 词：Clusterzyme Sustained delivery Reactive oxygen species Hippo pathway Rabbit anterior cruciate ligament transection model 

分 类 号：O64[理学—物理化学]