Bimetallic clusterzymes-loaded dendritic mesoporous silica particle regulate arthritis microenvironment via ROS scavenging and YAP1 stabilization

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 Au₂₄Cu₁. 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.