Coordination-Driven Self-Assembly of Metal Ion-Antisense Oligonucleotide Nanohybrids for Chronic Bacterial Infection Therapy.

Bacterial infection poses a significant challenge to wound healing and skin regeneration, leading to substantial economic burdens on patients and society. Therefore, it is crucial to promptly explore and develop effective methodologies for bacterial infections. Herein, we propose a novel approach for synthesizing nanostructures based on antisense oligonucleotides (ASOs) through the coordination-driven self-assembly of Zn2+ with ASO molecules. This approach aims to provide effective synergistic therapy for chronic wound infections caused by Staphylococcus aureus (S. aureus). The resulting hybrid nanoparticles successfully preserve the structural integrity and biological functionalities of ASOs, demonstrating excellent ASO encapsulation efficiency and bioaccessibility. In vitro antibacterial experiments reveal that Zn-ASO NPs exhibit antimicrobial properties against Escherichia coli, Staphylococcus aureus, and Bacillus subtilis. This antibacterial ability is attributed to the high concentration of metal zinc ions and the generation of high levels of reactive oxygen species. Additionally, the ftsZ-ASO effectively inhibits the expression of the ftsZ gene, further enhancing the antimicrobial effect. In vivo antibacterial assays demonstrate that the Zn-ASO NPs promote optimal skin wound healing and exhibit favorable biocompatibility against S. aureus infections, resulting in a residual infected area of less than 8%. This combined antibacterial strategy, which integrates antisense gene therapy and metal-coordination-directed self-assembly, not only achieves synergistic and augmented antibacterial outcomes but also expands the horizons of ASO coordination chemistry. Moreover, it addresses the gap in the antimicrobial application of metal-coordination ASO self-assembly, thereby advancing the field of ASO-based therapeutic approaches.

Photothermally Enhanced Cascaded Nanozyme-Functionalized Black Phosphorus Nanosheets for Targeted Treatment of Infected Diabetic Wounds.

Due to the limitations of H2 O2 under physiological conditions and defective activity, nanozyme-catalyzed therapy for infected diabetic wound healing is still a huge challenge. Here, this work designs a novel multifunctional hybrid glucose oxidase (GOx)-CeO2 @black phosphorus (BP)/Apt nanosheet that features GOx and CeO2 dual enzyme loading with photothermal enhancement effect and targeting ability for the treatment of infected wounds in type II diabetic mice. Combined with the photothermal properties of the BP nanosheets, the cascade nanozyme effect of GOx and CeO2 is extremely enhanced. The synergistic effect of peroxidase activity and photothermal therapy with targeting aptamer allows for overcoming the catalytic defects of nanozyme and significantly improving in vitro bacterial inhibition rate with 99.9% and 97.8% for Staphylococcus aureus and Escherichia coli, respectively, as well as enhancing in vivo antibacterial performance with the lowest wound remained (0.05%), reduction of infiltration inflammatory cells, and excellent biocompatibility. Overall, this work builds a nanodelivery system with a powerful therapeutic approach, incorporating self-supplying H2 O2 synergistic photothermal and real-time wound monitoring effect, which holds profound potential as a clinical treatment for infected diabetic wounds.

Discovery of novel potent PI3K/mTOR dual-target inhibitors based on scaffold hopping: Design, synthesis, and antiproliferative activity.

The PI3K/AKT/mTOR pathway is one of the most common dysregulated signaling cascade responses in human cancers, playing a crucial role in cell proliferation and angiogenesis. Therefore, the development of anticancer drugs targeting the PI3K and mTOR pathways has become a research hotspot in cancer treatment. In this study, the PI3K selective inhibitor GDC-0941 was selected as a lead compound, and 28 thiophenyl-triazine derivatives with aromatic urea structures were synthesized based on scaffold hopping, serving as a novel class of PI3K/mTOR dual inhibitors. The most promising compound Y-2 was obtained through antiproliferative activity evaluation, kinase inhibition, and toxicity assays. The results showed that Y-2 demonstrated potential inhibitory effects on both PI3K kinase and mTOR kinase, with IC50 values of 171.4 and 10.2 nM, respectively. The inhibitory effect of Y-2 on mTOR kinase was 52 times greater than that of the positive drug GDC-0941. Subsequently, the antitumor activity of Y-2 was verified through pharmacological experiments such as AO staining, cell apoptosis, scratch assays, and cell colony formation. The antitumor mechanism of Y-2 was further investigated through JC-1 experiments, real-time quantitative PCR, and Western blot analysis. Based on the above experiments, Y-2 can be identified as a potent PI3K/mTOR dual inhibitor for cancer treatment.