Targeting the ROS-ferroptosis-inflammation cycle with a nanozyme-functionalized hydrogel for intervertebral disc repair.

Abstract

Intervertebral disc degeneration is a major cause of low back pain and is driven by a vicious cycle of reactive oxygen species (ROS), ferroptosis, and inflammation, afflicting millions of people worldwide. Breaking this cycle represents a significant therapeutic challenge. Here, we develop a ROS-responsive hydrogel loading a resident nanozyme system composed of nucleus pulposus cell membrane-coated black phosphorus@cerium oxide to disrupt this degenerative cascade. Specifically, the nanozyme exhibits a self-sustaining cerium redox cycle due to the incorporation of black phosphorus nanosheets into cerium oxide, conferring durable antioxidant capacity for scavenging ROS. Furthermore, it suppresses the inflammatory cytokine IL6 by inhibiting HuR-mediated mRNA stabilization, thereby blocking the pro-inflammatory and pro-ferroptotic IL6/STAT3 axis. Together, this dual mechanism enables our nanozyme-functionalized hydrogel to break the ROS-ferroptosis-inflammation feedback loop, thus effectively promoting structural and functional disc repair.