Designing Single-Atom Active Sites on sp2 -Carbon Linked Covalent Organic Frameworks to Induce Bacterial Ferroptosis-Like for Robust Anti-Infection Therapy.

With the threat posed by drug-resistant pathogenic bacteria, developing non-antibiotic strategies for eradicating clinically prevalent superbugs remains challenging. Ferroptosis is a newly discovered form of regulated cell death that can overcome drug resistance. Emerging evidence shows the potential of triggering ferroptosis-like for antibacterial therapy, but the direct delivery of iron species is inefficient and may cause detrimental effects. Herein, an effective strategy to induce bacterial nonferrous ferroptosis-like by coordinating single-atom metal sites (e.g., Ir and Ru) into the sp2 -carbon-linked covalent organic framework (sp2 c-COF-Ir-ppy2 and sp2 c-COF-Ru-bpy2 ) is reported. Upon activating by light irradiation or hydrogen peroxide, the as-constructed Ir and Ru single-atom catalysts (SACs) can significantly expedite intracellular reactive oxygen species burst, enhance glutathione depletion-related glutathione peroxidase 4 deactivation, and disturb the nitrogen and respiratory metabolisms, leading to lipid peroxidation-driven ferroptotic damage. Both SAC inducers show potent antibacterial activity against Gram-positive bacteria, Gram-negative bacteria, clinically isolated methicillin-resistant Staphylococcus aureus (MRSA), and biofilms, as well as excellent biocompatibility and strong therapeutic and preventive potential in MRSA-infected wounds and abscesses. This delicate nonferrous ferroptosis-like strategy may open up new insights into the therapy of drug-resistant pathogen infection.

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.

An Optimally Designed Engineering Exosome-Reductive COF Integrated Nanoagent for Synergistically Enhanced Diabetic Fester Wound Healing.

Oxidative stress and local overactive inflammation have been considered major obstacles in diabetic wound treatment. Although antiphlogistic tactics have been reported widely, they are also challenged by pathogen contamination and compromised angiogenesis. Herein, a versatile integrated nanoagent based on 2D reductive covalent organic frameworks coated with antibacterial immuno-engineered exosome (PCOF@E-Exo) is reported to achieve efficient and comprehensive combination therapy for diabetic wounds. The E-Exo is collected from TNF-α-treated mesenchymal stem cells (MSCs) under hypoxia and encapsulated cationic antimicrobial carbon dots (CDs). This integrated nanoagent not only significantly scavenges reactive oxygen species and induces anti-inflammatory M2 macrophage polarization, but also stabilizes hypoxia-inducible factor-1α (HIF-1α). More importantly, the PCOF@E-Exo exhibits intriguing bactericide capabilities toward Gram-negative, Gram-positive, and drug-resistant bacteria, showing favorable intracellular bacterial destruction and biofilm permeation. In vivo results demonstrate that the synergetic impact of suppressing oxidative injury and tissue inflammation, promoting angiogenesis and eradicating bacterial infection, could significantly accelerate the infected diabetic fester wound healing with better therapeutic benefits than monotherapy or individual antibiotics. The proposed strategy can inspire further research to design more delicate platforms using the combination of immunotherapy with other therapeutic methods for more efficient ulcerated diabetic wounds treatments.

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.

Injectable In Situ Self-Cross-Linking Hydrogels Based on Hemoglobin, Carbon Quantum Dots, and Sodium Alginate for Real-Time Detection of Wound Bacterial Infection and Efficient Postoperative Prevention of Tumor Recurrence.

Postoperative wound repair of solid tumors resection, which is afflicted by the complex tumor microenvironment (TME) and associated with the bacterial infection, is worsening and demands prompt solutions. Meanwhile, the tumor recurrence is frequently seen during the subsequent treatment due to intraoperative bleeding. For effective postoperative cancer therapy, nanoscale carriers occur as innovative and sensitive tools for monitoring the wound state, avoiding bacterial infection, and restraining tumor recurrence. Herein, a multifunctional sodium alginate (SA) hydrogel immobilizing hemoglobin (Hb) and pH-sensitive fluorescent changing carbon quantum dots (CQDs) is rationally designed. The multifunctionalization of obtained alginate@hemoglobin@CQDs hydrogel (SA@Hb@CQDs) simultaneously consists of detection, hemostasis, and chemodynamic therapy (CDT) with monitoring of wound pH based on CQDs, stanching triggered from SA hydrogel, and Fenton reaction induced by Hb. We demonstrated that SA@Hb@CQDs can stop bleeding quickly, collect wound status information in real-time, and avert bacterial infection as well as inhibit local tumor recurrence effectively. Therefore, our work provides a promising combination approach for postoperative tumor therapy.