Injectable ROS/pH-Responsive Hydrogel for Synergistic Chemo-Photodynamic Tumor Therapy and Enhanced Wound Healing

Conventional cancer treatments often result in tissue loss, incomplete tumor excision, infections, and systemic toxicity, severely impacting patient recovery. These complications frequently involve excessive reactive oxygen species (ROS) generation and persistent inflammation, pathological features also characteristic of burn wounds and postoperative tumor sites. To address this, an injectable ROS/pH-responsive hydrogel integrating localized tumor therapy and wound healing is developed. The hydrogel is fabricated via Schiff base crosslinking of a thioketal-based ROS-cleavable linker with aldehyde-functionalized hyaluronic acid, enabling degradation under oxidative and acidic conditions. The hydrogel demonstrates mechanical robustness, excellent biocompatibility, and stimulus-triggered, on-demand drug release. In a breast tumor model, the designed hydrogel facilitates controlled co-delivery of a chemotherapeutic agent 5-fluorouracil (5-FU) and a photosensitizer precursor 5-aminolevulinic acid (ALA), and ensures precise, sustained drug release, achieving synergistic chemo-photodynamic therapy and superior tumor inhibition. Given the pathological similarities between tumor resection wounds and burn injuries, a second-degree burn model is employed to assess the hydrogel's regenerative performance under ROS-rich, inflammation-prone conditions. The hydrogel enables localized antioxidant drug N-acetyl-L-cysteine (NAC) delivery and non-mechanical, on-demand removal. These findings highlight the potential of this multifunctional hydrogel as a minimally invasive, dual-purpose platform for managing cancer-associated tissue injuries and oxidative stress-mediated wound healing.