Self-stiffening polysaccharide hydrogel targeting ferroptosis reverses intervertebral disc degeneration via iron ions chelation and Nrf2/GPX4 pathway

Intervertebral disc degeneration (IDD) remains an essential challenge in the clinic. Previous studies have confirmed that persistent inflammation and extracellular matrix (ECM) degradation contribute to the progression of IDD. Inhibiting ferroptotic function is essential for preventing ferroptosis-mediated inflammation and breaking the vicious cycle of ECM degradation. In addition, optimizing the mechanical strength required for physiological maintenance of the ECM is equally important. Herein, this study identifies the potential role of ferroptosis in the pathogenesis of IDD via the bioinformatics analysis, and we thus proposed a novel concept of self-stiffening hydrogel, which enables first to suppress ferroptosis, next to improve inflammatory micro-environment, and finally to optimize mechanical properties to facilitate migration of nucleus pulposus cells. As such, we prepared a self-stiffening hydrogel composed of chitosan/oxidized hyaluronic acid hydrogel (CS/OHA) and curcumin (Cur)-loaded metal-organic frameworks coated by macrophage membrane (Cur-MNPs). The precursor has the potential to decoy inflammatory cytokines as broad-spectrum inflammatory factor inhibitors via coated macrophage membranes. Meanwhile, acidic IDD micro-environment can trigger the specific release of Cur to inhibit ferroptosis-related pathway for alleviating inflammation and restoring the metabolic homeostasis of ECM. Furthermore, the Schiff-base moieties within the hydrogel can scavenge free ferrous ions to mitigate iron overload, converting the unfavorable factors that cause ferroptosis into favorable ligands that optimize mechanical strength. In summary, the novel approach provides a promising paradigm for IDD treatment.