Enzyme-Responsive COF-Based Thiol-Targeting Nanoinhibitor for Curing Bacterial Infections

Pathogen infections impose severe challenges in clinical practice, especially for patients infected with antibiotic-resistant microbes. The thioredoxin (Trx) system in Gram-positive bacteria serves as an ideal antimicrobial target for novel medicine design due to the structural differences from corresponding system in mammals. However, a backup thiol-dependent antioxidant glutathione (GSH) system limits the effectiveness of drugs in many Gram-negative bacteria. Herein, we synthesize a thiol-targeting nanoinhibitor based on an enzyme-responsive covalent organic framework (COF) coloaded with silver nanoparticles (AgNPs) and ebselen (EBS) (Ag-TA-CON@EBS@PEG) to exert synergistic antibacterial effects. Since azoreductase can dissociate the enzyme-responsive COF, we adopt this strategy to achieve the accurate release of EBS and Ag+ at infection sites. Our research identifies that the functionalized nanoinhibitor shows excellent bactericidal performance for Gram-positive and Gram-negative bacteria in vitro and exhibits low toxicity to normal cells. Besides, the nanoinhibitor presents favorable biocompatibility, anti-inflammatory property, and effective wound healing ability in mice. This paper provides a promising clinical strategy for synergistic antibacterial therapy and enhanced wound healing properties via an optimized combination of the targeted nanomedicines with an intelligent drug conveying platform.