ROS-balancing-engineered bio-heterojunction hydrogel accelerated the infected bone regeneration based on Sono-chemo dynamic therapy

Hypoxic deep-seated infections in refractory environments impede wound healing and exacerbate antibiotic resistance. Sonodynamic therapy (SDT) shows promise in combating pathogenic bacteria; however, the excessive reactive oxygen species (ROS) generated during the process often induce severe inflammatory responses, hindering tissue regeneration. To overcome these limitations, we have developed a multifunctional hydrogel, inspired by the dynamic regulatory mechanisms of rhizobia. GSH-SF/PeMA/MXene-TiO 2 (SP-MT) hydrogel was synthesized through the thiol-ene click chemistry mechanism. Methacrylated pectin (PeMA) and GSH-modified silk fibroin (GSH-SF) were combined with MXene-TiO 2 addition. This hydrogel exhibited favorable injectability, mechanical properties, swelling and degradation performance. In addition, this hydrogel can employ ultrasound-triggered dynamic ROS modulation to enable spatiotemporal regulation of antibacterial activity and promote tissue regeneration, effectively addressing the dual challenges of infection management and oxidative stress. Under ultrasound stimulation, SP-MT hydrogel can rapidly eradicate bacteria by disrupting membrane integrity and electron transport chains (ETCs) while simultaneously generating substantial ROS. Once the ultrasound stimulation ceased, the hydrogel and its degradation products eliminated residual ROS. In vivo studies further demonstrated that the nanohydrogel can accelerate soft tissue regeneration and periodontal bone regeneration by eradicating bacterial biofilms, promoting angiogenesis, and activating the TGF-β/SMAD signaling pathway. Therefore, this work introduces a novel strategy for equipping hydrogels with programmed antibacterial and anti-inflammatory functionalities, providing an innovative solution for treating deep-seated infections, particularly in periodontitis therapy. • Ultrasound-triggered antibacterial and ROS modulation: MXene-TiO 2 hydrogel utilizes ultrasound to dynamically modulate reactive oxygen species (ROS) for controlled antibacterial therapy, effectively addressing infection and oxidative stress. • Multiple antibacterial mechanism: Under ultrasound stimulation, hydrogel rapidly eliminates bacteria by disrupting membrane, electron transport chains, and generating ROS; once the ultrasound stops, hydrogel neutralizes residual ROS through its degradation products. • Enhanced tissue regeneration and wound healing: In vivo studies demonstrate that hydrogel accelerates wound healing and periodontal bone regeneration by eradicating bacterial biofilms, activating the TGF-β/SMAD pathway, and promoting angiogenesis.