Xanthan gum-based protocatechuic acid grafted carboxymethyl chitosan hydrogel with injectable, spraying, self-healing, and enhanced antioxidant properties

Abstract Overcoming the limitations of conventional antioxidants in treating oxidative stress-related neurodegenerative diseases (NDs) remains a critical challenge, thus more effective antioxidant strategies need to be studied urgently. To address this, we developed a novel pH-responsive drug-delivery hydrogel, PCA-g-CMCS/OXG, by grafting protocatechuic acid (PCA) onto carboxymethyl chitosan (CMCS) via amide bonds and blending it with oxidized xanthan gum (OXG) to form dynamic imine bonds. The conjugate PCA-g-CMCS achieved an unprecedented grafting efficiency of 785.3 mg g −1 through optimized reactant ratios, pH, and reaction time. And the multifunctional hydrogel PCA-g-CMCS/OXG offers three key advantages: (1) rapid tunable gelation time (10–110 s) and robust mechanical/rheological properties enabling injectable and sprayable applications; (2) self-healing capability and sustained pH-responsive PCA release over 15 d, ensuring long-term therapeutic efficacy; and (3) superior cytoprotection, as the hydrogel exhibited excellent biocompatibility with SH-SY5Y neuronal cells and significantly increased cell viability to 76.60% from H 2 O 2 -induced oxidative damage (vs. 48.61% for control, p < 0.01). Therefore, the smart Schiff’s base hydrogel is a drug loaded material with great clinical application prospect for the treatment of NDs.