Self-regulating neohesperidin/silk fibroin composite aerogel for enhanced wound healing via pH-responsive release

Effective wound healing and tissue regeneration are serious challenges in wound repair. Diseases or external stimuli that affect the body can generate excessive free radicals, which can trigger oxidative stress, inhibit wound healing, and lead to the formation of chronic wounds. Wound healing inhibition can be overcome by regulating the redox balance between reactive oxygen species (ROS) and antioxidants. Neohesperidin (Ne), a plant flavonoid compound with potent antioxidant properties, shows promise in mitigating oxidative stress and supporting wound healing. Here, we developed a novel aerogel dressing (MT-LCA + SF-Ne) by integrating silk fibroin (SF) and Ne into modified cellulose aerogels. The SF-mediated continuous delivery combined with the dual antioxidant/anti-inflammatory effects of Ne results in a sustained-release therapeutic system for wound microenvironment modulation. The aerogel was optimized by tuning its composition, SF concentration, and Ne loading, endowing it with suitable mechanical strength, thermal stability, and biocompatibility, while enabling pH-responsive Ne release aligned with wound healing dynamics. The aerogel disrupted the ROS-inflammation cascade and downregulated the M1/M2 macrophage ratio, thereby enhancing cell proliferation and migration, and demonstrating robust anti-inflammatory and antioxidant properties <i>in vitro</i>. Collectively, this study establishes a bioactive delivery system with pH-tunable release, anti-inflammatory, antioxidant, and tissue-regenerative capabilities and provides new insights into the application of lignocellulosic materials in wound care, holding great potential for clinical translation.