Diabetes constitutes a significant and escalating global concern. According to estimations by the International Diabetes Federation, the number of diabetics is projected to approach 600 million by 2035 [1,2]. Given its chronic nature, many patients are plagued by the development of diabetic foot ulcers, resulting in the distressing reality that roughly 20% of those experiencing acute symptoms necessitate amputation [3]. Currently, the management of diabetic wounds encounters formidable challenges, as a single treatment approach fails to adequately address the multifaceted nature of this complex metabolic disease [4,5]. Successful wound healing entails a delicate balance between adequate inflammation during the reactive phase to ensure swift bacterial clearance, thereby averting the onset of bacterial resistance and biofilm formation [5], [6], [7], [8]. In the subsequent reparative phase, resolution of chronic inflammation and activation of repair cells emerge as pivotal factors [9]. The orchestrated differentiation of macrophages accompanies this intricate process [10]. Unfortunately, the orderly transformation from pro- to anti-inflammatory process is disrupted by hyperglycemia-induced physiological changes in diabetes, including vasculopathy, tissue hypoxia, accumulation of advanced glycation end products, immune dysregulation, etc. [11], [12], [13]. Consequently, achieving an effective treatment for diabetes-infected wounds necessitates the on-demand balancing of pro- and anti-inflammation within the infected area.

Biofilm is another challenge in the management of diabetic wounds. Bacterial colonies in biofilms are well protected by extracellular polymeric substances (EPS) formed by adhesion of various biomacromolecules [14]. These barriers prevent drug penetration and suppress the inflammatory environment to promote bacterial survival, so that clinical antibiotics are often limited by biofilms when treating wounds [15]. Recently, glucose oxidase (GOx)-triggered cascade catalytic antibacterial therapy has become popular because it converts “harmful” glucose into hydroxyl radicals (•OH) to eliminate bacteria [16], [17], [18], [19]. Considering that the lower pH of the catalytic product is conducive to the Fenton reaction, the content of ferrous ions (Fe2+) in the catalyst would determine the yield of •OH, thereby affecting the sterilization efficiency. However, there are many inconveniences in the storage and usage of fragile GOx and Fe2+. With the development of advanced enzyme immobilization or biomineralization methods, GOx-based nanocomposites have shown significant effects in improving the stability and activity of enzymes compared to their free states [20,21]. On this basis, suitable stabilizers could be integrated to prevent Fe2+ oxidization during the construction of enzyme carriers.

Based on the above considerations, a nanoparticle-mediated “one-two punch” strategy was implemented here to treat diabetic-infected wounds by effectively killing bacteria during the inflammatory phase and promoting tissue repair during the repair phase (Scheme 1). Azithromycin (AZM) is a macrolide antibiotic with a long half-life and anti-inflammatory properties [22]. Through an AZM-involved biomimetic mineralization method, GOx was immobilized in iron sulfide nanoparticles (termed GOx@FexSy/AZM). Due to the enzyme immobilization and coordination interaction between AZM and Fe2+ in GOx@FexSy/AZM, GOx and Fe2+ are decently protected, which is critical for cascade catalytic therapy. At the infectious stage, massive •OH were derived from GOx and Fe2+ mediated glucose conversion, combined with AZM and high-level H2S gas release to efficiently eliminate biofilm [23]. Furthermore, accompanied by the consumption of glucose, the AZM and low-level H2S in tissues worked together to promote inflammatory regression via prolonged inhibition of pro-inflammatory transcription factors (AP-1 and NF-κB) within macrophages, as well as reprograming macrophages from pro- to anti-inflammatory phenotypes. This one-two punch strategy catered to various needs in the different healing processes of infected wounds, reversing the inflammatory microenvironment at the right time to accelerate the repair process.