Bioengineered Versatile Heterojunctions as Stress Busters Targeting Matrix Degradation and Ferroptosis for Osteoarthritis Therapy

Osteoarthritis (OA) is a chronic joint disease characterized by degeneration of articular cartilage, with the underlying mechanism being the inability of chondrocytes to maintain homeostasis in response to the changing stress. The stress response triggered by excess ROS from various factors is critical in regulating chondrocyte survival and fate. In this study, 2D Mo_4/3B_2-X MBene and cerium-gallic acid metal-polyphenol network (MPN) together with cartilage-targeted shell of hyaluronic acid and WYRGRL (HW) are utilized to development bio-heterojunction MBene@MPN-HW (MBM-HW) through self-assembly. The bio-heterojunction MBM-HW not only demonstrates superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) enzyme mimicking capabilities to effectively scavenge excess ROS, but also exhibits dual-responsive release and cartilage-targeting properties. Importantly, both in vivo and in vitro experiments indicate that MBM-HW could alleviate chondrocyte oxidative stress, protect mitochondrial function, suppress cartilage matrix degeneration and ferroptosis, thereby slowing the progression of OA. Mechanistically, it is demonstrated that MBM-HW could attenuate Perk/eIF2α cascade mediated integrated stress response to effectively restrain matrix degeneration and ferroptosis, thereby maintaining chondrocyte homeostasis. Overall, this work underscores the robust stress-relieving capacity of bio-heterojunction MBM-HW, providing a novel approach for the treatment of OA.