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)- κ B, 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.