ROS-responsive hydrogel for treating pulpitis: Localized immunometabolic regulation by dimethyl itaconate promotes reparative dentin formation

A ROS-responsive injectable hydrogel for DMI delivery is developed. • DMI suppresses inflammation and oxidative stress in DPSCs. • DMI does not directly promote odontogenesis under inflammation. • DMI restores odontogenesis via macrophage-mediated modulation. • The hydrogel enhances reparative dentin formation in vivo . Pulpitis is a common inflammatory disease of the dental pulp in which excessive inflammation and oxidative stress severely compromise the regenerative capacity of dental pulp stem cells (DPSCs), posing a major challenge for successful vital pulp therapy. Herein, we report an immunometabolic strategy that combines dimethyl itaconate (DMI) with a reactive oxygen species (ROS)-responsive injectable hydrogel to modulate the inflammatory microenvironment and promote functional pulp regeneration. We demonstrated that DMI effectively suppressed lipopolysaccharide (LPS)-induced inflammatory cytokine expression and ROS accumulation in DPSCs. Notably, DMI did not directly enhance odontogenic differentiation under inflammatory conditions; instead, it indirectly restored the odontogenic potential of DPSCs by attenuating macrophage-mediated inflammation. To enable localized and sustained delivery of DMI, a dual-crosslinked SADA/CMBA hydrogel was developed based on dynamic boronic ester bonds and ionic coordination, allowing ROS-triggered drug release while maintaining structural integrity and biocompatibility. In vitro studies confirmed the hydrogel’s favorable cytocompatibility, anti-inflammatory and antioxidant effects. Furthermore, in an LPS-induced rat pulpitis model, the DMI-loaded hydrogel significantly reduced pulpal inflammation and facilitated reparative dentin formation at the pulp exposure site. Collectively, this study introduces an immunometabolic and microenvironment-responsive therapeutic design for pulpitis treatment and highlights the potential of ROS-adaptive biomaterials to enhance the outcomes of vital pulp therapy. Download: Download high-res image (130KB) Download: Download full-size image DMI@SADA/CMBA hydrogel application for treating pulpitis