A chitosan-based hydrogel with ultrasound-driven immuno-sonodynamic therapeutic effect for accelerated bacterial...

Sonodynamic therapy has attracted much attention as a noninvasive treatment for deep infections. However, it is challenging to achieve high antibacterial activity for hydrogels under ultrasonic irradiation due to the relatively weak sono-catalysis capability of sonosensitizers. Herein, an ultrasound-responsive antibacterial hydrogel (Fe₃O₄/HA/Ber-LA) composed of Fe₃O₄-grafted-Berberine, chitosan molecules modified with L-arginine and poly (vinyl alcohol) is prepared for enhanced sonodynamic therapy and immunoregulation. The formation of heterojunction between berberine and Fe₃O₄ with different work function promotes the charge separation and electron flow and disrupts the conjugated structure of berberine, causing a significant decrease in the band gap, eventually enhancing the sonocatalytic activity. The combination of berberine with Fe₃O₄ also significantly improves the oxygen adsorption energy, enabling more O₂ molecules to react with the electron-rich regions on the surface of Fe₃O₄ to generate more reactive oxygen species (ROS). L-arginine grafted in the hydrogel is catalyzed by the ROS to release nitric oxide, which not only possesses antibacterial activity, but also positively affects macrophage M1 polarization to display potent phagocytosis to Staphylococcus aureus, thus achieving immuno-sonodynamic therapy. Hence, Fe₃O₄/HA/Ber-LA hydrogel under ultrasound irradiation shows excellent antibacterial activity. Furthermore, the antioxidative activity and anti-inflammatory effect of berberine released from the hybrid hydrogel induces macrophages to polarize towards the anti-inflammatory M2 status as infection comes under control, thus accelerating the wound healing. The hybrid hydrogel based on the immuno-sonodynamic therapy may be an extraordinary candidate for the treatment of deep infections.