Bioactive oxidized silk fibroin hydrogel enables low-dose puerarin therapy for chemotherapy-induced oral mucositis

Chemotherapy-induced oral mucositis (CIOM), affecting up to 60% of patients with head and neck cancers after chemotherapy, is driven by reactive oxygen species (ROS) overproduction, inflammation, and bacterial infection, while current analgesic and anti-inflammatory treatments remain limited by poor targeting, low bioavailability, and insufficient efficacy. To address these challenges, we developed a puerarin-loaded oxidized silk fibroin hydrogel (Pue@OxSF) for the rapid repair of CIOM. Oxidative modification increased the β-sheet content and antioxidant capacity of SF, while markedly shortening its gelation time, thereby enabling the formation of multifunctional OxSF hydrogel for efficient Pue delivery. The incorporation of Pue into OxSF reduced the required drug dosage and generated a synergistic therapeutic effect. The resulting Pue@OxSF hydrogel exhibited efficient ROS scavenging ability and concurrently induced macrophage polarization toward an M2-like phenotype, thereby creating an anti-inflammatory microenvironment favorable for tissue repair. In addition, the Pue@OxSF hydrogel demonstrated excellent antibacterial efficacy while simultaneously facilitating cellular migration and promoting angiogenic responses. In a rat CIOM models, Pue@OxSF significantly accelerated mucosal wound healing and showed outstanding biocompatibility across both in vitro and in vivo evaluations. These results indicate that Pue@OxSF hydrogel holds considerable promise as a therapeutic platform for treating CIOM as well as other inflammation-related disorders.