A Manganese-Luteolin Co-loaded Antioxidant Hydrogel for Synergistic Alleviation of Oxidative Stress and Immunomodulation in Intervertebral Disc Degeneration

Intervertebral disc degeneration (IVDD) is a multifactorial degenerative disorder primarily driven by oxidative stress, chronic inflammation, and progressive extracellular matrix (ECM) breakdown. Current therapeutic approaches largely aim to alleviate symptoms but remain ineffective in halting or reversing the underlying pathological processes. To address this challenge, we designed an injectable, pH-responsive manganese–luteolin hydrogel (Mn-LU@Gel) capable of concurrently mitigating oxidative stress and inflammatory responses within the intervertebral disc microenvironment. Synthesized via Schiff base chemistry, Mn-LU@Gel demonstrated robust antioxidant activity and controlled release behavior under acidic conditions. In vitro, the hydrogel effectively scavenged reactive oxygen species (ROS) in macrophages and nucleus pulposus cells, reprogramming macrophage polarization from a pro-inflammatory M1 phenotype toward an anti-inflammatory M2 state. This immunomodulatory shift resulted in the downregulation of pro-inflammatory cytokines, along with enhanced expression of anabolic ECM markers and suppression of catabolic enzymes, as verified by Western blot and immunofluorescence assays. In vivo, administration of Mn-LU@Gel in a rat model of IVDD preserved disc height, hydration, and structural integrity, thereby maintaining ECM homeostasis. Collectively, these findings reveal Mn-LU@Gel as a multifunctional therapeutic platform that integrates redox regulation and immune modulation, offering a promising strategy for the biological restoration of intervertebral disc tissue.