A Guanosine-Quadruplex Hydrogel as Cascade Reaction Container Consuming Endogenous Glucose for Infected Wound Treatment-A Study in Diabetic Mice

Diabetic foot ulcers infected with antibiotic-resistant bacteria form a severe complication of diabetes. Antimicrobial-loaded hydrogels are used as a dressing for infected wounds, but the ongoing rise in the number of antimicrobial-resistant infections necessitates new, nonantibiotic based designs. Here, a guanosine-quadruplex (G(4))-hydrogel composed of guanosine, 2-formylphenylboronic acid, and putrescine is designed and used as a cascade-reaction container. The G(4)-hydrogel is loaded with glucose-oxidase and hemin. The first cascade-reaction, initiated by glucose-oxidase, transforms glucose and O-2 into gluconic acid and H2O2. In vitro, this reaction is most influential on killing Staphylococcus aureus or Pseudomonas aeruginosa in suspension, but showed limited killing of bacteria in biofilm-modes of growth. The second cascade-reaction, however, transforming H2O2 into reactive-oxygen-species (ROS), also enhances killing of biofilm bacteria due to hemin penetration into biofilms and interaction with eDNA G-quadruplexes in the biofilm matrix. Therewith, the second cascade-reaction generates ROS close to the target bacteria, facilitating killing despite the short life-time of ROS. Healing of infected wounds in diabetic mice proceeds faster upon coverage by these G(4)-hydrogels than by clinically common ciprofloxacin irrigation. Moreover, local glucose concentrations around infected wounds decrease. Concluding, a G(4)-hydrogel loaded with glucose-oxidase and hemin is a good candidate for infected wound dressings, particularly in diabetic patients.