A supramolecular hydrogel dressing with antibacterial, immunoregulation, and pro-regeneration ability for biofilm-associated wound healing.

Chronic wound treatment has emerged as a significant healthcare concern worldwide due to its substantial economic burden and the limited effectiveness of current treatments. Effective management of biofilm infections, regulation of excessive oxidative stress, and promotion of tissue regeneration are crucial for addressing chronic wounds. Hydrogel stands out as a promising candidate for chronic wound treatment. However, its clinical application is hindered by the difficulty in designing and fabricating easily and conveniently. To overcome these obstacles, we present a supermolecular G-quadruplex hydrogel with the desired multifunction via a dynamic covalent strategy and Hoogsteen-type hydrogen bonding. The G-quadruplex hydrogel is made from the self-assembly of guanosine, 2-formylphenyboronic acid, polyethylenimine, and potassium chloride, employing dynamic covalent strategy and Hoogsteen-type hydrogen bonding. In the acidic/oxidative microenvironment associated with bacterial infections, the hydrogel undergoes controlled degradation, releasing the polyethylenimine domain, which effectively eliminates bacteria. Furthermore, nanocomplexes comprising guanosine monophosphate and manganese sulfate are incorporated into the hydrogel skeleton, endowing it with the ability to scavenge reactive oxygen species and modulate macrophages. Additionally, the integration of basic fibroblast growth factor into the G-quadruplex skeleton through dynamic covalent bonds facilitates controlled tissue regeneration. In summary, the facile preparation process and the incorporation of multiple functionalities render the G-quadruplex hydrogel a highly promising candidate for advanced wound dressing. It holds great potential to transition from laboratory research to clinical practice, addressing the pressing needs of chronic wound management.

Dynamic covalent nano-networks comprising antibiotics and polyphenols orchestrate bacterial drug resistance reversal and inflammation alleviation.

New antimicrobial strategies are urgently needed to meet the challenges posed by the emergence of drug-resistant bacteria and bacterial biofilms. This work reports the facile synthesis of antimicrobial dynamic covalent nano-networks (aDCNs) composing antibiotics bearing multiple primary amines, polyphenols, and a cross-linker acylphenylboronic acid. Mechanistically, the iminoboronate bond drives the formation of aDCNs, facilitates their stability, and renders them highly responsive to stimuli, such as low pH and high H2O2 levels. Besides, the representative A1B1C1 networks, composed of polymyxin B1(A1), 2-formylphenylboronic acid (B1), and quercetin (C1), inhibit biofilm formation of drug-resistant Escherichia coli, eliminate the mature biofilms, alleviate macrophage inflammation, and minimize the side effects of free polymyxins. Excellent bacterial eradication and inflammation amelioration efficiency of A1B1C1 networks are also observed in a peritoneal infection model. The facile synthesis, excellent antimicrobial performance, and biocompatibility of these aDCNs potentiate them as a much-needed alternative in current antimicrobial pipelines.

Tumor Cell-Derived Microparticles Induced by Methotrexate Augment T-cell Antitumor Responses by Downregulating Expression of PD-1 in Neutrophils.

Neutrophils act as a "double-edged sword" in the tumor microenvironment by either supporting or suppressing tumor progression. Thus, eliciting a neutrophil antitumor response remains challenging. Here, we showed that tumor cell-derived microparticles induced by methotrexate (MTX-MP) acts as an immunotherapeutic agent to activate neutrophils, increasing the tumor-killing effect of the cells and augmenting T-cell antitumor responses. We found that lactate induced tumor-associated neutrophils to elevate expression of programmed cell death protein 1 (PD-1) and that PD-1+ neutrophils had the properties of N2 neutrophils and suppressed T-cell activation through PD-1/programmed death-ligand 1 (PD-L1) signaling. By performing ex vivo experiments, we found that MTX-MPs-activated neutrophils had reduced surface expression of PD-1 as a result of PD-1 internalization and degradation in the lysosomes, leading to the cells showing a decreased capacity to suppress T-cell responses. In addition, we also found that MTX-MP-activated neutrophils released neutrophil elastase which could kill tumor cells and disrupt tumor stroma, leading to increased T-cell infiltration. Furthermore, using a combination of anti-PD-L1 and MTX-MPs, we observed that long-term survival increased in a mouse model of lung cancer. Collectively, these findings highlight the potential use of a combination of anti-PD-L1 and MTX-MPs to enhance the therapeutic effect of anti-PD-L1 alone.