Engineering Multifunctional Nanozymes to Reprogram Oxidative Stress and Inflammation in Chronic Wounds

Qingyan Li,1,* Weilin Zheng,2,* Jingge Cheng,1,* Bo Li,1 Yutian Lei,1 Huilong Guo,1 Youshan Xv,3 Jiaming Huang,4 Xiaoxing Liao1,5 1Emergency and Disaster Medicine center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong Province, People’s Republic of China; 2Department of Hepatobiliary and Gastrointestinal Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, People’s Republic of China; 3The Huiqiao Medical Center (International Medical Service) of Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, People’s Republic of China; 4Department of Hepatobiliary and Gastrointestinal Surgery, Shenzhen Guangming District People’s Hospital, Shenzhen, Guangdong Province, People’s Republic of China; 5The Institute of Emergency Care and Resuscitation, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoxing Liao, Email [email protected] Jiaming Huang, Email [email protected]: Diabetic wounds represent a growing clinical challenge worldwide, characterized by persistent immune dysregulation and excessive inflammation that lead to impaired healing and chronic progression.Methods: To address this, we developed a composite nanosystem, termed Ru@ACEI, composed of ruthenium-incorporated hollow mesoporous silica nanoparticles loaded with angiotensin-converting enzyme inhibitors (ACEIs).Results: The Ru@ACEI nanoparticles exhibit dual enzyme-mimetic activities (superoxide dismutase and catalase), effectively scavenging excess reactive oxygen species (ROS). This activity reduces cellular apoptosis and promotes endothelial cell proliferation. Following cellular uptake, Ru@ACEI catalyzes the decomposition of peroxides into water and oxygen, thereby suppressing the NLRP3/Caspase-3/Caspase-9 apoptosis pathway. The consequent improvement in endothelial cell survival helps reverse local hyperinflammation in diabetic wounds.Conclusion: Collectively, these findings demonstrate that the Ru@ACEI nanosystem accelerates diabetic wound healing by mitigating the inflammatory microenvironment and downregulating the expression of pro-inflammatory factors, offering a promising therapeutic strategy for managing chronic diabetic wounds.Keywords: diabetic wound, nanoenzyme, apoptosis, ROS-scavenge, anti-inflammatory microenvironment