A Pullulan-Based Multiresponsive Self-Healing Hydrogel with Anti-Inflammatory, Photothermal Antibacterial, and Macrophage-Repolarization Functions for Infected Wound Healing

Infected wounds are characterized by pathogenic infiltration that can initiate inflammatory responses and lead to severe complications. In this work, we developed a dynamically cross-linked, multiresponsive hydrogel designed to facilitate effective bacterial eradication, inflammation mitigation, and the healing of infected wounds. Based on a unique design utilizing gelatin and 4-formylphenylboronic acid-modified pullulan (PF) loaded with baicalein-iron chelate nanoparticles (Bai-Fe NPs), this hydrogel is characterized by its dynamic sensitivity to pH, reactive oxygen species (ROS), and temperature, as well as its robust mechanical strength, self-healing ability, and excellent tissue adhesiveness. Furthermore, under 808 nm laser irradiation, the incorporated Bai-Fe NPs exhibit a photothermal effect to eradicate bacteria and alleviate inflammation. In vivo experiments have shown that this hydrogel clears bacteria and promotes macrophage repolarization from M1 to M2, thereby reprogramming the inflammatory response and restoring microenvironmental balance, significantly enhancing the regenerative capacity of infected wounds. Overall, this system intelligently responds to the wound microenvironment (pH, ROS, and temperature) to trigger drug release, while its photothermal activity provides a simultaneous antibacterial effect. This multimechanistic synergy enables precise treatment beyond the capabilities of conventional single-response hydrogels, highlighting its promising therapeutic potential for infected wounds.