A one-two punch strategy for diabetic wound management based on an antibiotic-hybrid biomineralized iron sulfide...

Bacterial infection and immune imbalance are the primary culprits behind chronic wounds in individuals with diabetes, impeding the progression of damaged tissues towards normal healing. To achieve a harmonious balance between pro- and anti-inflammation within these infected areas, herein, we propose a one-two punch strategy for on-demand therapy of diabetes-infected wounds, utilizing an azithromycin (AZM)-hybrid nanocomposite termed GOx@Fe_xS_y/AZM. During the infective stage, the nanocomposite facilitates the production of ROS, coupled with the burst release of AZM and H₂S gas, effectively dismantling biofilms and achieving rapid sterilization. Subsequently, the hyperinflammatory response induced by antibiosis is significantly mitigated through the synergistic action of tissue H₂S and the prolonged half-life of AZM. These components inhibit the activity of pro-inflammatory transcription factors (AP-1 and NF-κB) within macrophages, thereby promoting the polarization of macrophages towards a reparative M2 phenotype and facilitating tissue remodeling. By catering to the diverse requirements of wound healing at different stages, this nanocomposite accelerates a sensible transition from inflammation to the reparative phase. In summary, this one-two punch strategy gives an instructive instance for procedural treatment of diabetes wound infection. STATEMENT OF SIGNIFICANCE: The treatment of diabetic wound infection presents two major challenges: the diminished antibacterial efficacy arising from biofilm formation and bacterial resistance, as well as the inadequate transition of the wound microenvironment from pro-inflammatory to anti-inflammatory states after bacterial clearance. In this work, a biomineralized iron sulfide nanocomposite was prepared to mediate cascade catalytic (ROS storm) / antibiotic (AZM) / gas (H₂S) triple-synergetic antibacterial therapy during the initial stage of bacterial infection, achieving the goal of rapid bactericidal effect; Subsequently, the residual H₂S and long half-life AZM would inhibit the key pro-inflammatory transcription factors and promote the macrophages polarization to reparative M2, which effectively mediated tissue repair after hyperinflammatory reactions, leading to orderly treatment of hyperglycemic infected wounds.