Double Hits with Bioactive Nanozyme Based on Cobalt-Doped Nanoglass for Acute and Diabetic Wound Therapies Through Anti-Inflammatory and Pro-Angiogenic Functions

Abstract

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 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 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 wound). 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-1α. Finally, we compared the in vivo efficacy of CoNZ with 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.

Note:
Funding declaration: This work was supported by the National Research Foundation of Korea (NRF) via a grant funded by the Ministry of Science and ICT (NRF-2019R1C1C1002490, 2018R1A2B3003446, 2021R1l1A1A0104910412, and 2018K1A4A3A01064257 (Global Research Development Center Program)).

Conflict of Interests: HW Kim is an editorial board member/editor-in-chief for Bioactive Materials and was not involved in the editorial review or the decision to publish this article. All authors declare that there are no competing interests.

Ethical Approval: . All surgical procedures were performed in accordance with the guidelines approved by the Institutional Animal Care and Use Committee at Dankook University (approval no. DKU-18-032), Republic of Korea.

Keywords: Diabetic wound, Nanozyme, anti-inflammation, angiogenesis, Therapeutic materials