Abstract: Effective treatment of intervertebral disc degeneration with biomaterials remains a challenge, owing to the difficulty in simultaneously overcoming oxidative stress and its associated cascades in the nucleus pulposus microenvironment, which includes cellular senescence, apoptosis, infiammation, and extracel-lular matrix (ECM) degradation. To address these issues, a multifunctional hydrogel (HG-QNT) loaded with transforming growth factor-β 1 (TGF-β 1) and quercetin-based nanoparticles (QUNPs) is developed through borate ester bonding and Schiff base reaction-induced crosslinking. Specifically, QUNPs fabri-cated via coordination and hydrophobic interactions endow the hydrogel with extraordinary antioxidative properties. Benefiting from the multi-dynamic crosslinking, the hydrogel achieves self-healing, mechani-cal stability, and pH-responsive release of QUNPs and TGF-β 1. The HG-QNT hydrogel is demonstrated to enhance the proliferation of encapsulated nucleus pulposus cells, thereby providing an ideal platform for cell transplantation. The cooperative antioxidation of QUNPs and the hydrogel carrier renders HG-QNT effective in mitigating oxidative stress, resulting in the suppression of cellular senescence, mitochondrial dysfunction, apoptosis, excessive inflammation, and abnormal catabolism. Afterwards, TGF-β 1 and QUNPs act in synergy with the hydrogel to restore the anabolic/catabolic balance by enhancing ECM synthesis. Overall, the strategy orchestrating multiple modulation by HG-QNT hydrogel shows great potential for application in intervertebral disc regeneration.

Key words: Intervertebral disc regeneration, Multiple modulation, Multifunctional hydrogel, Quercetin-based nanoparticles, TGF-β1