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.

Automated summary

In this study, we developed a thiol-targeting nanoinhibitor based on an enzyme-responsive covalent organic framework, which was co-loaded with silver nanoparticles and ebselen, to achieve synergistic antibacterial effects. The nanoinhibitor showed excellent bactericidal performance for both Gram-positive and Gram-negative bacteria in vitro, and exhibited low toxicity to normal cells. Additionally, it demonstrated favorable biocompatibility, anti-inflammatory properties, and effective wound healing abilities in mice.