Targeting the ROS-ferroptosis-inflammation cycle with a nanozyme-functionalized hydrogel for intervertebral disc
Yanqiu Wang1,2, Lu Tan3, Yi Yang4
1Department of Orthopedics, Xinqiao Hospital, Army Medical University, Chongqing, China.
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.
Insights
This study introduces a novel hydrogel loaded with a nanozyme system to combat intervertebral disc degeneration. The treatment effectively breaks the cycle of reactive oxygen species (ROS), ferroptosis, and inflammation, promoting disc repair.
Area of Science:
- Biomaterials Science
- Regenerative Medicine
- Nanotechnology
Background:
- Intervertebral disc degeneration (IVDD) is a primary cause of low back pain, driven by a destructive cycle involving reactive oxygen species (ROS), ferroptosis, and inflammation.
- Current therapeutic strategies face challenges in disrupting this complex degenerative cascade effectively.
Purpose of the Study:
- To develop a ROS-responsive hydrogel system incorporating a novel nanozyme to target and disrupt the vicious cycle in IVDD.
- To evaluate the nanozyme's capacity to scavenge ROS, suppress inflammation, and inhibit ferroptosis for promoting disc repair.
Main Methods:
- Fabrication of a ROS-responsive hydrogel loaded with a nanozyme system: nucleus pulposus cell membrane-coated black phosphorus@cerium oxide.
- Characterization of the nanozyme's dual mechanism: sustained ROS scavenging via a black phosphorus-enhanced cerium redox cycle and suppression of the IL6/STAT3 inflammatory axis.
- Assessment of the hydrogel's efficacy in promoting structural and functional disc repair in a preclinical model.
Main Results:
- The nanozyme demonstrated durable antioxidant capacity by scavenging ROS through a self-sustaining cerium redox cycle.
- The system effectively suppressed the inflammatory cytokine IL6 by inhibiting HuR-mediated mRNA stabilization, thereby blocking the IL6/STAT3 axis.
- The nanozyme-functionalized hydrogel successfully broke the ROS-ferroptosis-inflammation feedback loop, leading to significant disc repair.
Conclusions:
- The developed ROS-responsive hydrogel with a dual-action nanozyme offers a promising therapeutic approach for intervertebral disc degeneration.
- This strategy effectively disrupts the key pathological cycle, paving the way for enhanced structural and functional recovery of degenerated discs.
