Ultrasmall Cu2I2 nanoclusters trigger metabolic-epigenetic reprogramming and endogenous antioxidant systems for alleviating osteoarthritis

•For the first time, nanomaterials were used in Temporomandibular joint (TMJ) osteoarthritis as a metabolic-epigenetic regulator.•Based on ultrasmall size and Cu active center. Cu2I2 nanoclusters exhibit high biocompatibility and ROS-scavenging activity.•Cu2I2 nanoclusters can downregulate ATP level, inhibit S-adenosylmethionine (SAM) metabolic pathway, resulting in global hypomethylation, and then activate anti-osteoclastogenesis gene.•Cu2I2 nanoclusters can activate endogenous antioxidant systems and metabolic-epigenetic reprogramming in subchondral bone with articular injection, contributing to bone remodeling in OA. Temporomandibular joint (TMJ) osteoarthritis (OA) affects millions of people worldwide, characterized by imbalance metabolism, excess reactive oxygen species (ROS), aberrant epigenetic alterations and so on. Currently, analgesics and anti-inflammatory drugs are mainly used for treatment, but they only alleviate symptoms. Here, we designed a ultrasmall copper-based nanoclusters agent (copper iodide coordination, Cu2I2), which exhibited remarkable ROS-scavenging activities. And the antioxidant properties of Cu2I2 nanoclusters (Cu2I2 NCs) were achieved by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Excitingly, Cu2I2 NCs exhibited excellent metabolic-epigenetic regulation property via reprogramming energy metabolism to inhibit S-adenosylmethionine (SAM)-production metabolic pathway and contributing to the global hypomethylation mediated by Dnmt3a. Then, the expression of anti-osteoclastogenic genes was upregulated. Consistent with in vitro observations, Cu2I2 NCs efficiently alleviated subchondral bone destruction of TMJ OA in rats. Altogether, this study not only provides a novel nanoclusters agent for TMJ OA treatment that can activate endogenous antioxidant systems, but also reveals the significance and feasibility of therapeutic strategies to break the bridge between metabolic and epigenetic regulation.