Inflammatory Cytokine Signature‐Guided Sequential Therapy for Osteoarthritis Through Biomarker‐Informed Immunomodulation and Regenerative Stimulation

Osteoarthritis (OA) is a chronic inflammatory degenerative disease characterized by persistent cytokine dysregulation, cartilage matrix degradation, and impaired regeneration. Disease‐associated inflammatory cytokine signatures, particularly IL‐1β–driven networks, may serve as actionable biomarkers for evaluating disease activity and guiding therapeutic strategies. However, biomarker‐informed treatment sequencing remains insufficiently explored. Here, we developed a biomarker‐informed sequential therapeutic platform integrating inflammatory cytokine modulation and regenerative stimulation for OA treatment. A diclofenac sodium (DS)–loaded AAM/SBMA‐based double‐network ionic conductive adhesive hydrogel was engineered to provide temporally coordinated intervention, enabling early inflammatory regulation followed by regenerative stimulation. In an IL‐1β–induced inflammatory chondrocyte model, DS‐mediated modulation of inflammatory biomarker activity was associated with suppression of NF‐κB signaling, reduced oxidative stress, and downregulated catabolic biomarkers, including IL‐1β and MMP13, thereby restoring a regenerative‐permissive microenvironment. Subsequent electrical stimulation enhanced anabolic responses by promoting aggrecan and collagen type II (COLII) expression. Compared with single interventions, the sequential strategy improved chondrocyte function, extracellular matrix preservation, and cartilage repair outcomes, which were further validated in ex vivo cartilage explants. This study demonstrates that inflammatory biomarker network normalization can regulate regenerative responsiveness and therapeutic timing, providing a precision medicine‐oriented framework for chronic inflammatory disease management.