A Zn-MOF-GOx-based cascade nanoreactor promotes diabetic infected wound healing by NO release and microenvironment regulation

Guangli Xiang; Bingjie Wang; Wenshang Zhang; Yu Dong; Jiaojiao Tao; Aijia Zhang; Rui Chen; Tianze Jiang; Xia Zhao

doi:10.1016/j.actbio.2024.05.015

A Zn-MOF-GOx-based cascade nanoreactor promotes diabetic infected wound healing by NO release and microenvironment regulation

Acta Biomater. 2024 May 9:S1742-7061(24)00253-8. doi: 10.1016/j.actbio.2024.05.015. Online ahead of print.

Authors

Guangli Xiang¹, Bingjie Wang¹, Wenshang Zhang¹, Yu Dong¹, Jiaojiao Tao¹, Aijia Zhang¹, Rui Chen¹, Tianze Jiang¹, Xia Zhao²

Affiliations

¹ 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.
² 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. Electronic address: zhaoxia@ouc.edu.cn.

PMID: 38729545
DOI: 10.1016/j.actbio.2024.05.015

Abstract

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 (H₂O₂) to enable Arg-to release nitric oxide (NO) for inflammation regulation, providing a suitable microenvironment for wound healing. Zinc ions (Zn²⁺) 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 Zn²⁺ 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.

Keywords: Cascade catalysis; Diabetic wound healing; Gas therapy; Glucose oxidase (GOx); Metal organic frameworks (MOFs).