Key Laboratory of Marine Drugs, Ministry of Education, Shandong Key Laboratory of Glycoscience and Glycotechnology, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
Key Laboratory of Marine Drugs, Ministry of Education, Shandong Key Laboratory of Glycoscience and Glycotechnology, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China.
Acta Biomater. 2024 Jul 1;182:245-259. doi: 10.1016/j.actbio.2024.05.015. Epub 2024 May 9.
Diabetic wound healing is a great clinical challenge due to the microenvironment of hyperglycemia and high pH value, bacterial infection and persistent inflammation. Here, we develop a cascade nanoreactor hydrogel (Arg@Zn-MOF-GOx Gel, AZG-Gel) with arginine (Arg) loaded Zinc metal organic framework (Zn-MOF) and glucose oxidase (GOx) based on chondroitin sulfate (CS) and Pluronic (F127) to accelerate diabetic infected wound healing. GOx in AZG-Gel was triggered by hyperglycemic environment to reduce local glucose and pH, and simultaneously produced hydrogen peroxide (HO) to enable Arg-to release nitric oxide (NO) for inflammation regulation, providing a suitable microenvironment for wound healing. Zinc ions (Zn) released from acid-responsive Zn-MOF significantly inhibited the proliferation and biofilm formation of S.aureus and E.coli. AZG-Gel significantly accelerated diabetic infected wound healing by down-regulating pro-inflammatory tumor necrosis factor (TNF)-α and interleukin (IL)-6, up-regulating anti-inflammatory factor IL-4, promoting angiogenesis and collagen deposition in vivo. Collectively, our nanoreactor cascade strategy combining "endogenous improvement (reducing glucose and pH)" with "exogenous resistance (anti-bacterial and anti-inflammatory)" provides a new idea for promoting diabetic infected wound healing by addressing both symptoms and root causes. STATEMENT OF SIGNIFICANCE: A cascade nanoreactor (AZG-Gel) is constructed to solve three key problems in diabetic wound healing, namely, hyperglycemia and high pH microenvironment, bacterial infection and persistent inflammation. Local glucose and pH levels are reduced by GOx to provide a suitable microenvironment for wound healing. The release of Zn significantly inhibits bacterial proliferation and biofilm formation, and NO reduces wound inflammation and promotes angiogenesis. The pH change when AZG-Gel is applied to wounds is expected to enable the visualization of wound healing to guide the treatment of diabetic wound. Our strategy of "endogenous improvement (reducing glucose and pH)" combined with "exogenous resistance (anti-bacterial and anti-inflammatory)" provides a new way for promoting diabetic wound healing.
糖尿病伤口愈合是一个巨大的临床挑战，原因是高血糖和高 pH 值、细菌感染和持续炎症的微环境。在这里，我们基于硫酸软骨素（CS）和泊洛沙姆（F127）开发了一种基于精氨酸（Arg）负载的锌金属有机骨架（Zn-MOF）和葡萄糖氧化酶（GOx）的级联纳米反应器水凝胶（Arg@Zn-MOF-GOx 水凝胶，AZG-Gel），以加速糖尿病感染性伤口愈合。AZG-Gel 中的 GOx 被高血糖环境触发，以降低局部葡萄糖和 pH 值，同时产生过氧化氢（HO），使 Arg 释放一氧化氮（NO）以调节炎症，为伤口愈合提供合适的微环境。从酸响应性 Zn-MOF 释放的锌离子（Zn）显著抑制了金黄色葡萄球菌和大肠杆菌的增殖和生物膜形成。AZG-Gel 通过下调促炎因子肿瘤坏死因子（TNF）-α和白细胞介素（IL）-6，上调抗炎因子 IL-4，促进血管生成和胶原沉积，显著加速糖尿病感染性伤口愈合。总之，我们的级联纳米反应器策略结合了“内源性改善（降低葡萄糖和 pH 值）”和“外源性抵抗（抗菌和抗炎）”，为解决糖尿病感染性伤口愈合的三个关键问题提供了一个新的思路。
