Immunomodulatory and Antioxidant Biomimetic Hydrogel Coloaded with Glycyrrhizic Acid and Copper Gallate for Synergistic Cartilage Regeneration

Abstract Articular cartilage lesions are persistently restrained by three interwoven pathological drivers: chronic inflammatory response, sustained oxidative stress, and progressive extracellular matrix (ECM) catabolism. Coupled with the inherently weak self-repair capacity of hyaline cartilage, effective therapeutic interventions for such injuries remain an unmet clinical demand owing to the inherently poor self-repair capacity of hyaline cartilage, effective therapeutic interventions remain an unmet clinical demand. Herein, we engineered a biomimetic composite hydrogel designated ECM/HAMA/GA@Cu-GA, which integrates decellularized cartilage extracellular matrix, methacrylated hyaluronic acid (HAMA), glycyrrhizic acid (GA), and copper gallate (Cu-GA). This integrated hydrogel platform simultaneously endows biomimetic mechanical support, potent anti-inflammatory and antioxidative bioactivities, as well as robust chondrogenic induction capacity. In vitro cellular evaluations verified the outstanding biocompatibility of the composite hydrogel. The biomaterial efficiently polarizes macrophages toward the anti-inflammatory M2 phenotype, suppresses the secretion of pro-inflammatory mediators and matrix-degrading proteases, and facilitates the migration and chondrogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Transcriptomic profiling suggested that its underlying molecular mechanisms may involve activation of the PI3K/Akt signaling cascade and blockade of the NF-κB-mediated inflammatory pathway. In vivo assessments using rat articular cartilage defect models demonstrated that the ECM/HAMA/GA@Cu-GA hydrogel achieves satisfactory synchronous regeneration of hyaline cartilage and subchondral bone at 4 and 8 weeks post-implantation, with superior regenerative performance relative to all control groups. Collectively, this multifunctional hydrogel enables comprehensive remodeling of the pathological joint microenvironment with favorable biosafety profiles, representing a translatable candidate strategy for clinical management of cartilage degenerative disorders.