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 ...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.展开更多
Tendinopathy is a prevalent musculoskeletal disorder,accounting for over 30%of musculoskeletal lesions.However,current therapeutic strategies for tendinopathy are limited and often yield unsatisfactory clinical outcom...Tendinopathy is a prevalent musculoskeletal disorder,accounting for over 30%of musculoskeletal lesions.However,current therapeutic strategies for tendinopathy are limited and often yield unsatisfactory clinical outcomes.Therefore,there is a critical need to explore novel therapeutic approaches with minimal side effects for tendinopathy and its early lesions.In this study,we successfully designed and synthesized a copper(I)-based nanocluster,named Cu_(11),which possesses remarkable enzyme-like and ROS-scavenging activities.This unique combination of properties qualifies Cu_(11)as an attractive anti-inflammatory and anti-ROS agent.The Cu_(11)clusterzymes specifically target mitochondria,effectively scavenging excessive reactive oxygen species(ROS)and reducing oxidative stress.Furthermore,Cu_(11)clusterzymes inhibit the activation of key signaling pathways involved in inflammation,namely tumor necrosis factor(TNF),mitogen-activated protein kinase(MAPK),and nuclear factor(NF)-κB,leading to a decrease in the release of proinflammatory cytokines.Excitingly,our in vivo experiments using a collagenase-induced acute Achilles tendinopathy model demonstrated that Cu_(11)clusterzymes effectively alleviate inflammation and oxidative stress,without causing systemic toxicity.This study highlights the potential of copper-based clusterzymes as therapeutic agents for the treatment of Achilles tendinopathy and other inflammatory diseases.The unique enzyme-like and ROS-scavenging activities of Cu_(11)make it a promising candidate for further development and clinical translation.展开更多
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).
文摘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.
基金the Open Project of Shandong Provincial Health Commission Key Laboratory of Oral Diseases and Tissue Regeneration(No.2023KF001)China Postdoctoral Science Foundation(No.2023M732281)+1 种基金the National Natural Science Foundation of China(Nos.82301108,and 82071135)the Natural Science Foundation of Shandong Province(No.ZR2021MH230).
文摘Tendinopathy is a prevalent musculoskeletal disorder,accounting for over 30%of musculoskeletal lesions.However,current therapeutic strategies for tendinopathy are limited and often yield unsatisfactory clinical outcomes.Therefore,there is a critical need to explore novel therapeutic approaches with minimal side effects for tendinopathy and its early lesions.In this study,we successfully designed and synthesized a copper(I)-based nanocluster,named Cu_(11),which possesses remarkable enzyme-like and ROS-scavenging activities.This unique combination of properties qualifies Cu_(11)as an attractive anti-inflammatory and anti-ROS agent.The Cu_(11)clusterzymes specifically target mitochondria,effectively scavenging excessive reactive oxygen species(ROS)and reducing oxidative stress.Furthermore,Cu_(11)clusterzymes inhibit the activation of key signaling pathways involved in inflammation,namely tumor necrosis factor(TNF),mitogen-activated protein kinase(MAPK),and nuclear factor(NF)-κB,leading to a decrease in the release of proinflammatory cytokines.Excitingly,our in vivo experiments using a collagenase-induced acute Achilles tendinopathy model demonstrated that Cu_(11)clusterzymes effectively alleviate inflammation and oxidative stress,without causing systemic toxicity.This study highlights the potential of copper-based clusterzymes as therapeutic agents for the treatment of Achilles tendinopathy and other inflammatory diseases.The unique enzyme-like and ROS-scavenging activities of Cu_(11)make it a promising candidate for further development and clinical translation.
