Ultrasmall Antioxidant Copper Nanozyme to Enhance Stem Cell Microenvironment for Promoting Diabetic Wound Healing

Biao Hou,1,* Chengyuan Li,2,* Fen Yang,3,* Wanjun Deng,1 Chao Hu,1 Changxiong Liu,1 Yanming Chen,1 Xiangjun Xiao,1 Xiongjie Huang,1 Jun Deng,1,4 Songlin Xie1 1Department of Hand and Foot Microsurgery, The Affiliated Nanhua Hospital, Hengyang Medical College, University of South China, Hengyang, Hunan, People’s Republic of China; 2Department of Pathology, School of Basic Medicine, Central South University, Changsha, Hunan, People’s Republic of China; 3Department of Infectious Diseases, The Affiliated Nanhua Hospital, Hengyang Medical College, University of South China, Hengyang, Hunan, People’s Republic of China; 4Institute of Burn Research, Southwest Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Chongqing Key Laboratory for Disease Proteomics, Army Medical University, Chongqing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Songlin Xie; Jun Deng, Email [email protected]; [email protected]: Stem cell therapy is a promising approach for treating chronic diabetic wounds. However, its effectiveness is significantly limited by the high oxidative stress environment and persistent inflammation induced by diabetes. Strategies to overcome these challenges are essential to enhance the therapeutic potential of stem cell therapy.Methods: Cu5.4O ultrasmall nanoparticles (Cu5.4O-USNPs), known for their excellent reactive oxygen species (ROS) scavenging properties, were utilized to protect adipose-derived stem cells (ADSCs) from oxidative stress injury. In vitro experiments were conducted to evaluate the viability, paracrine activity, and anti-inflammatory capabilities of ADSCs loaded with Cu5.4O-USNPs under oxidative stress conditions. In vivo experiments in diabetic mice were performed to assess the therapeutic effects of Cu5.4O-USNP-loaded ADSCs on wound healing, including their impact on inflammation, collagen synthesis, angiogenesis, and wound closure.Results: ADSCs treated with Cu5.4O-USNPs showed significantly enhanced viability, paracrine activity, and anti-inflammatory properties under oxidative stress conditions in vitro. In diabetic mice, Cu5.4O-USNP-loaded ADSCs reduced inflammatory responses in wound tissues, promoted collagen synthesis and angiogenesis, and accelerated diabetic wound healing. These findings suggest that Cu5.4O-USNPs effectively mitigate the adverse effects of oxidative stress and inflammation, enhancing the therapeutic efficacy of ADSCs.Conclusion: This study presents a simple and effective approach to improve the therapeutic potential of stem cell therapy for diabetic wounds. By incorporating Cu5.4O-USNPs, the antioxidative and anti-inflammatory capabilities of ADSCs are significantly enhanced, offering a promising strategy for ROS-related tissue repair and chronic wound healing.Keywords: stem cell therapy, Cu5.4O-USNPs, ADSCs, inflammatory environment