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.

Light-Activated Biodegradable Covalent Organic Framework-Integrated Heterojunction for Photodynamic, Photothermal, and Gaseous Therapy of Chronic Wound Infection.

Chronic wound healing, impeded by bacterial infections and drug resistance, poses a threat to global human health. Antibacterial phototherapy is an effective way to fight microbial infection without causing drug resistance. Covalent organic frameworks (COFs) are a class of highly crystalline functional porous carbon-based materials composed of light atoms (e.g., carbon, nitrogen, oxygen, and borane), showing potential applications in the biomedical field. Herein, we constructed porphyrin-based COF nanosheets (TP-Por CON) for synergizing photodynamic and photothermal therapy under red light irradiation (e.g., 635 nm). Moreover, a nitric oxide (NO) donor molecule, BNN6, was encapsulated into the pore volume of the crystalline porous framework structure to moderately release NO triggered by red light irradiation for realizing gaseous therapy. Therefore, we successfully synthesized a novel TP-Por CON@BNN6-integrated heterojunction for thoroughly killing Gram-negative bacteria Escherichia coli and Gram-positive bacteria Staphylococcus aureus in vitro. Our research identified that TP-Por CON@BNN6 has favorable biocompatibility and biodegradability, low phototoxicity, anti-inflammatory properties, and excellent mice wound healing ability in vivo. This study indicates that the TP-Por CON@BNN6-integrated heterojunction with multifunctional properties provides a potential strategy for COF-based gaseous therapy and microorganism-infected chronic wound healing.