Injectable Nanocomposite Hydrogels for Intervertebral Disc Degeneration: Combating Oxidative Stress, Mitochondrial Dysfunction, and Ferroptosis

Abstract Intervertebral disc degeneration (IVDD) is a major cause of low back pain, where oxidative stress and mitochondrial dysfunction are key contributors. Additionally, ferroptosis, an iron‐dependent form of cell death, is identified as a critical mechanism in IVDD pathogenesis. Herein, the therapeutic potential of gallic acid (GA)‐derived PGA‐Cu nanoparticles, enhanced with functional octapeptide (Cys‐Lys‐His‐Gly‐ d ‐Arg‐ d ‐Tyr‐Lys‐Phe, SS08) to build the mitochondria‐targeted nanoparticles (PGA‐Cu@SS08), and embedded within a hydrogel matrix to form a nanocomposite hydrogel, is explored. The nanoparticles show targeted localization within mitochondria, effectively scavenging reactive oxygen species and preserving mitochondrial function. The abundant phenolic hydroxyl groups present on the nanoparticle surface, along with the histidine residue of the SS08 peptide, endow these entities with the capacity to chelate iron. Through RNA sequencing analysis, it is discovered that PGA‐Cu@SS08 activates the NRF2 signaling pathway, mitigating ferroptosis. It also reduces iron overload by inhibiting the autophagy of iron storage proteins. Additionally, the nanocomposite hydrogels exhibit excellent biocompatibility and biodegradability, along with enhanced mechanical properties that improve intervertebral disc (IVD) performance. PGA‐Cu@SS08 is continuously released from these hydrogels, restoring IVD height and maintaining tissue hydration levels, thus facilitating future applications for alleviating IVDD.