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 Cu₁₁, which possesses remarkable enzyme-like and ROS-scavenging activities. This unique combination of properties qualifies Cu₁₁ as an attractive anti-inflammatory and anti-ROS agent. The Cu₁₁ clusterzymes specifically target mitochondria, effectively scavenging excessive reactive oxygen species (ROS) and reducing oxidative stress. Furthermore, Cu₁₁ 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 Cu₁₁ 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 Cu₁₁ make it a promising candidate for further development and clinical translation.