A Pathological Microenvironment-Responsive Catalytic Carbon Nanodots Release Platform Intercepting the ROS-Inflammation Cascade to Alleviate Intervertebral Disc Degeneration.

Localized oxidative stress and chronic inflammation driven by excessive accumulation of reactive oxygen species (ROS) represent central pathogenic forces that initiate and perpetuate the degenerative cascade underlying intervertebral disc degeneration (IVDD). Here, it is developed a pathological microenvironment-responsive catalytic carbon nanodot delivery platform (PPOD@CeCDs) featuring dual reversible covalent cross-linking mediated by phenylboronate ester and Schiff base bonds, which selectively senses the acidic and highly oxidative milieu characteristic of IVDD to enable on-demand release of cerium-doped carbon nanodots (CeCDs), thereby intercepting the ROS-driven inflammatory cascade at its oxidative origin. PPOD@CeCDs exhibits favorable injectability, controllable degradability, biocompatibility, and robust antioxidant activity, together with stable intradiscal retention and stimulus-responsive release under pathological conditions. In vitro, PPOD@CeCDs protects nucleus pulposus (NP) cells from oxidative injury, suppresses inflammation amplification by modulating the ROS-driven PI3K-Akt-NF-κB signaling axis, regulates macrophage polarization, and preserves extracellular matrix homeostasis. In a rat model of IVDD, intradiscal injection of PPOD@CeCDs mitigates matrix degradation and promotes structural restoration of degenerative discs. Collectively, by integrating a microenvironment-responsive hydrogel with catalytically active carbon nanodots, this strategy sustainably intercepts ROS-driven inflammatory cascades and offers a mechanistically defined, translationally promising therapeutic approach for IVDD.