Double hits with bioactive nanozyme based on cobalt-doped nanoglass for acute and diabetic wound therapies through anti-inflammatory and pro-angiogenic functions

Regeneration of pathological wounds, such as diabetic ulcers, poses a significant challenge in clinical settings, despite the widespread use of drugs. To overcome clinical side effects and complications, drug-free therapeutics need to be developed to promote angiogenesis while overcoming inflammation to restore regenerative events. This study presents a novel bioactive nanozyme based on cobalt-doped nanoglass (namely, CoNZ), which exhibits high enzymatic/catalytic activity while releasing therapeutic ions. Cobalt oxide "Co3O4" tiny crystallites produced in situ through a chemical reaction with H2O2 within CoNZ nanoparticles play a crucial role in scavenging ROS. Results showed that CoNZ-treatment to full-thickness skin wounds in mice significantly accelerated the healing process, promoting neovascularization, matrix deposition, and epithelial lining while reducing pro-inflammatory signs. Notably, CoNZ was highly effective in treating pathological wounds (streptozotocin-induced diabetic wounds). Rapid scavenging of ROS by CoNZ and down-regulation of pro-inflammatory markers while up-regulating tissue healing signs with proliferative cells and activated angiogenic factors contributed to the observed healing events. In vitro experiments involving CoNZ-cultures with macrophages and endothelial cells exposed to high glucose and ROS-generating conditions further confirmed the effectiveness of CoNZ. CoNZ-promoted angiogenesis was attributed to the release of cobalt ions, as evidenced by the comparable effects of CoNZ-extracted ionic medium in enhancing endothelial migration and tubule formation via activated HIF-1 & alpha;. Finally, we compared the in vivo efficacy of CoNZ with the clinically-available drug deferoxamine. Results demonstrated that CoNZ was as effective as the drug in closing the diabetic wound, indicating the potential of CoNZ as a novel drug-free therapeutic approach.