ROS/pH dynamically responsive injectable hydrogel ameliorates disc degeneration by re-establishing the oxidative stress microenvironment

Intervertebral disc degeneration (IVDD) stands as a predominant cause of low back pain (LBP). The excessive accumulation of reactive oxygen species (ROS) represents a crucial pathophysiological mechanism involved in IVDD, which triggers oxidative stress in the microenvironment, resulting in apoptosis, inflammation, and metabolic imbalance of extracellular matrix (ECM). Here, we ingeniously devised an injectable hydrogel (CMC-PBA/ODEX/HMP@Lut) consisting of phenylboronic acid-modified carboxymethyl chitosan (CMC-PBA), oxidized dextran (ODEX), MnO₂ nanoparticles loaded with luteolin (HMP@Lut). The introduction of HMP@Lut as a nanofiller into hydrogels enabled the additional cross-linking of polymer networks through hydrogen bonding. The phenylborate ester bonds, hydrogen bonds, and Schiff base bonds conferred the ROS/pH dual-responsiveness to the hydrogel. It was designed to adapt to the acidic environment and effectively scavenged ROS, ameliorated apoptosis, inflammation and modulated ECM metabolic imbalances. In vitro, the hydrogel could inhibit oxidative stress of nucleus pulposus cells by modulating the PI3K/AKT/NF-κB signaling pathway, exerting anti-inflammatory and anti-apoptotic effects and reducing ECM degradation. In animal experiments, the hydrogel improved the microenvironment and promoted disc regeneration through its injectability, excellent biocompatibility and degradability. In brief, this multifunctional hydrogel endowed with dual response properties presents a new strategy for the IVDD treatment, which is promising for future clinical applications.