Injectable dual-drug hydrogel containing curcumin and glycyrrhizic acid for biofilm inhibition and immunomodulatory therapy in periodontitis

Periodontitis is a chronic inflammatory disease characterized by excessive oxidative stress, persistent bacterial biofilms, and progressive destruction of periodontal tissues. Current clinical treatments primarily focus on controlling bacterial infection but often show limited long-term efficacy due to unresolved immune dysregulation. Therefore, therapeutic strategies that simultaneously target microbial biofilms and the pathological immune microenvironment are urgently needed. In this study, we developed an injectable dual-drug hydrogel incorporating curcumin (CUR) and glycyrrhizic acid (GL) for the treatment of periodontitis. CUR was dissolved in melted polyethylene glycol distearate and then dispersed in an aqueous medium to form micelles (CURM). Compared to CUR, CURM exhibited improved solubility and stability, thereby displaying greatly enhanced antioxidative, anti-inflammatory, and antibacterial activities. CURM were subsequently embedded within a hydrogel self-assembled from glycyrrhizic acid and polyvinyl alcohol (GLH) to form a dual-drug hydrogel system (CURM@GLH). Experimental periodontitis was established in mice to test their in vivo effects. Owing to the intrinsic anti-inflammatory and antioxidative properties of glycyrrhizic acid, the hydrogel exhibited combined effects in regulating immune dysregulation. The CURM@GLH effectively protected cells from oxidative damage, reduced intracellular reactive oxygen species levels, promoted macrophage polarization from the proinflammatory M1 phenotype toward the pro-regenerative M2 phenotype, and downregulated proinflammatory cytokine expression. In a ligature-induced rat model of periodontitis, local administration of the hydrogel significantly alleviated periodontal oxidative stress and inflammation and markedly reduced alveolar bone resorption. This study presents an injectable dual-drug hydrogel, CURM@GLH, that integrates biofilm inhibition with immunomodulatory regulation, offering a promising host-directed therapeutic strategy for periodontitis. The proposed approach provides new insights into the design of multifunctional biomaterials for the treatment of chronic inflammatory diseases associated with biofilm persistence and immune imbalance.