An Endogenous Adenosine Triphosphate‐Activated Hydrogel Prodrug System for Healing Multidrug‐Resistant Bacteria Infected Diabetic Foot Ulcers

Abstract Current guidelines for addressing multidrug‐resistant bacteria‐infected diabetic foot ulcers (DFUs), a leading cause of disability and death among diabetes sufferers, still lack specificity. Such DFU lesions often experience delayed recovery, primarily due to the bacteria‐induced inflammation in the adverse diabetic microenvironment. Here, an endogenous adenosine triphosphate (ATP)‐responsive hydrogel prodrug platform (abbreviated as HSAQ3), which embeds hemoglobin@zeolitic imidazolate framework‐8 (Hb@ZIF‐8) nanoparticles in a prodrug (1‐naphthylacetic acid, NAA)‐loaded biopolymer matrix, targeting multidrug‐resistant bacterial infections in DFUs is presented. Initially, using a simple local injection, an HSAQ3 adhesive barrier triggered by UV light is applied to the wound. Concurrently, HSAQ3's composition, enriched with quaternary ammonium salt and phenylboronic acid groups, exhibits strong bacterial trapping capabilities, effectively capturing bacteria at the wound location within the hydrogel. Following this, ATP secreted by bacteria initiates the degradation of Hb@ZIF‐8, enabling the simultaneous interaction of the encapsulated NAA prodrug with Hb peroxidase. This process effectively produces reactive oxygen species (ROS) in situ, addressing their limited lifespan and diffusion range, thus guaranteeing a highly efficient bactericidal effect. This study unveils an innovative inorganic–organic hybrid prodrug system, leveraging endogenous ATP from bacteria for precise ROS generation, enhancing the healing of multidrug‐resistant bacterial infections in DFUs.