Hypoxia deactivates epigenetic feedbacks via enzyme-derived clicking proteolysis-targeting chimeras.

Epigenetic mediation through bromodomain and extraterminal (BET) proteins have progressively translated protein imbalance into effective cancer treatment. Perturbation of druggable BET proteins through proteolysis-targeting chimeras (PROTACs) has recently contributed to the discovery of effective therapeutics. Unfortunately, precise and microenvironment-activatable BET protein degradation content with promising tumor selectivity and pharmacological suitability remains elusive. Here, we present an enzyme-derived clicking PROTACs (ENCTACs) capable of orthogonally cross-linking two disparate small-molecule warhead ligands that recognize BET bromodomain-containing protein 4 (BRD4) protein and E3 ligase within tumors only upon hypoxia-induced activation of nitroreductase enzyme. This localized formation of heterobifunctional degraders promotes specific down-regulation of BRD4, which subsequently alters expression of epigenetic targets and, therefore, allows precise modulation of hypoxic signaling in live cells, zebrafish, and living mice with solid tumors. Our activation-feedback system demonstrates compelling superiorities and may enable the PROTAC technology with more flexible practicality and druggable potency for precision medicine in the near future.

Emerging strategies in developing multifunctional nanomaterials for cancer nanotheranostics.

Cancer involves a collection of diseases with a common trait - dysregulation in cell proliferation. At present, traditional therapeutic strategies against cancer have limitations in tackling various tumors in clinical settings. These include chemotherapeutic resistance and the inability to overcome intrinsic physiological barriers to drug delivery. Nanomaterials have presented promising strategies for tumor treatment in recent years. Nanotheranostics combine therapeutic and bioimaging functionalities at the single nanoparticle level and have experienced tremendous growth over the past few years. This review highlights recent developments of advanced nanomaterials and nanotheranostics in three main directions: stimulus-responsive nanomaterials, nanocarriers targeting the tumor microenvironment, and emerging nanomaterials that integrate with phototherapies and immunotherapies. We also discuss the cytotoxicity and outlook of next-generation nanomaterials towards clinical implementation.

Cyanine-Dyad Molecular Probe for the Simultaneous Profiling of the Evolution of Multiple Radical Species During Bacterial Infections.

Real-time monitoring of the evolution of bacterial infection-associated multiple radical species is critical to accurately profile the pathogenesis and host-defense mechanisms. Here, we present a unique dual wavelength near-infrared (NIR) cyanine-dyad molecular probe (HCy5-Cy7) for simultaneous monitoring of reactive oxygen and nitrogen species (RONS) variations both in vitro and in vivo. HCy5-Cy7 specifically turns on its fluorescence at 660 nm via superoxide or hydroxyl radical (O2.- , . OH)-mediated oxidation of reduced HCy5 moiety to Cy5, while peroxynitrite or hypochlorous species (ONOO- , ClO- )-induced Cy7 structural degradation causes the emission turn-off at 800 nm. Such multispectral but reverse signal responses allow multiplex manifestation of in situ oxidative and nitrosative stress events during the pathogenic and defensive processes in both bacteria-infected macrophage cells and living mice. Most importantly, this study may also provide new perspectives for understanding the bacterial pathogenesis and advancing the precision medicine against infectious diseases.

Near-Infrared Light Brightens Bacterial Disinfection: Recent Progress and Perspectives.

Bacterial infection is a universal threat to public health, which not only causes many serious diseases but also exacerbates the condition of the patients of cancer, pandemic diseases, e.g., COVID-19, and so on. Antibiotic therapy has been used to be an effective way for common bacterial disinfection. However, due to the misuse and abuse of antibiotics, more and more antibiotic-resistant bacteria have emerged as fatal threats to human beings. At present, more than 700,000 patients die every year with bacterial infections because of the lack of effective treatment. It is frustrating that the pace of development of antibiotics lags far behind that of bacterial resistance, with an estimation of 10 million deaths per year from bacterial infections after 2050. Facing such a rigorous challenge, approaches for bacterial disinfection are urgently demanded. The recently developed near-infrared (NIR) light-irradiation-based bacterial disinfection is highly promising to shatter bacterial resistance by employing NIR light-responsive materials as mediums to generate antibacterial factors such as heat, reactive oxygen species (ROS), and so on. This treatment approach is proved to be a potent candidate to accurately realize spatiotemporal control, while effectively eradicating multidrug-resistant bacteria and inhibiting antibiotic resistance. Herein, we summarize the latest progress of NIR light-based bacterial disinfection. Ultimately, current challenges and perspectives in this field are discussed.