Ultrasmall copper-based clusterzymes ameliorate Achilles tendinopathy by inhibiting acute oxidative stress

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.