Converting Bacterial Anti-Stress Metabolites into Bactericidal Agents Using a MOF Nanozyme for Targeted Treatment of Infected Diabetic Ulcers

Abstract Bacteria evolve sophisticated antistress systems to adapt to lethal conditions such as oxidative stress, and such defensive mechanisms confer them with tolerance against antibacterial therapies. However, whether endogenous antistress metabolites can be repurposed to convert bacterial self-protection into amplified antibacterial mechanisms remains largely unexplored. Here, we designed a galactosyl MOF nanozyme (Gal-MIL/GOx) that upregulates target-specifically the bacterial antistress metabolite, glutathione (GSH), which in turn accelerates cascade catalytic-amplified oxidative damage, facilitating the treatment of infected diabetic ulcers. In a mouse model of Pseudomonas aeruginosa (P. aeruginosa)-infected diabetic wounds, we demonstrated the targeted adhesion of Gal-MIL/GOx to bacteria via selective galactose-LecA interactions, thereby disrupting the integrity of the cell membrane. Notably, this process upregulated bacterial GSH levels and accelerated the cascade catalytic activity of the nanozyme. Significantly, the nanozyme initiated a sustained conversion of local glucose in diabetic wounds to generate high concentrations of H2O2 leading to bacterial membrane rupture. This resulted in a more pronounced leakage of bacterial GSH, which facilitated the conversion of H2O2 into the more toxic •OH, thus amplifying oxidative damage. Through a series of biochemical analyses, we confirmed that the nanozyme can effectively eliminate bacteria, alleviate localized hyperglycemia, and remodel immune homeostasis to promote tissue repair in diabetic mouse wounds. Our findings illustrate a new strategy where MOF nanozymes are used to convert bacterial antistress metabolites into a bactericidal amplifier, thus providing a new avenue for treating infected diabetic ulcers.