Thermosensitive Hydrogel Incorporating Prussian Blue Nanoparticles Promotes Diabetic Wound Healing via ROS Scavenging and Mitochondrial Function Restoration

Diabetic foot ulcer is a serious complication in diabetes patients, imposing a serious physical and economic burden to patients and to the healthcare system as a whole. Oxidative stress is thought to be a key driver of the pathogenesis of such ulcers. However, no antioxidant drugs have received clinical approval to date, underscoring the need for the further development of such medications. Hydrogels can be applied directly to the wound site, wherein they function to prevent infection and maintain local moisture concentrations, in addition to serving as a reservoir for the delivery of a range of therapeutic compounds with the potential to expedite wound healing in a synergistic manner. Herein, we synthesized Prussian blue nanoparticles (PBNPs) capable of efficiently scavenging reactive oxygen species (ROS) owing to their ability to mimic the activity of catalase (CAT), peroxidase (POD), and superoxide dismutase (SOD). In the context of in vitro oxidative stress, these PBNPs were able to protect against cytotoxicity, protect mitochondria from oxidative stress-related damage, and restore nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) pathway activity. To expand on these results in an in vivo context, we prepared a thermosensitive poly (d,l-lactide)-poly(ethylene glycol)-poly(d,l-lactide) (PDLLA-PEG-PDLLA) hydrogel (PLEL)-based wound dressing in which PBNPs had been homogenously incorporated, and we then used this dressing as a platform for controlled PBNP release. The resultant PBNPs@PLEL wound dressing was able to improve diabetic wound healing, decrease ROS production, promote angiogenesis, and reduce pro-inflammatory interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels within diabetic wounds. Overall, our results suggest that this PBNPs@PLEL platform holds great promise as a treatment for diabetic foot ulcers.