Ultrasound‐Triggered Diselenide Bonds Scission for On‐Demand Drug Release in Osteoarthritis Therapy

ABSTRACT Disruption of chondrocyte redox homeostasis is a critical pathogenic factor in osteoarthritis (OA). Selenium (Se), an essential trace element, helps maintain redox balance by regulating 25 selenoproteins in human tissues. Based on this, we developed a Se‐based OA treatment strategy using a novel ultrasound‐responsive hydrogel (HA‐Se hydrogel). This system employs hyaluronic acid (HA) as a matrix and integrates ultrasound‐responsive diselenide (Se─Se) bonds that act as an intelligent “on‐off” for precise spatiotemporal control of Se release at the lesion site. This promotes efficient conversion into bioactive selenoproteins, restoring redox homeostasis in the OA microenvironment. In vitro and in vivo results demonstrate that ultrasound‐triggered scission of Se─Se bonds facilitates on‐demand Se release. The released Se is converted into selenoproteins, which enhance antioxidant capacity, reduce ROS accumulation, and restore mitochondrial membrane potential, thereby inhibiting chondrocyte apoptosis, attenuating inflammation, and delaying OA progression. Furthermore, this system enhances SOX9 expression by activating the PI3K/AKT pathway, thereby activating COL2A1 and inhibiting MMP13 to regulate cartilage metabolism balance. In conclusion, the engineered HA‐Se hydrogel provides an effective solution for achieving controlled Se release in OA therapy. It represents a multi‐target treatment strategy combining anti‐oxidation, anti‐apoptosis, anti‐inflammation, and anti‐metabolic mechanisms, with significant clinical translation potential.