A Novel Cascade Nanoreactor Integrating Two-Dimensional Pd-Ru Nanozyme, Uricase and Red Blood Cell Membrane for Highly Efficient Hyperuricemia Treatment.

Nanozyme-based cascade reaction has emerged as an effective strategy for disease treatment because of its high efficiency and low side effects. Herein, a new and highly active two-dimensional Pd-Ru nanozyme is prepared and then integrated with uricase and red blood cell (RBC) membrane to fabricate a tandem nanoreactor, Pd-Ru/Uricase@RBC, for hyperuricemia treatment. The designed Pd-Ru/Uricase@RBC nanoreactor displayed not only good stability against extreme pH, temperature and proteolytic degradation, but also long circulation half-life and excellent safety. The nanoreactor can effectively degrade UA by uricase to allantoin and H2 O2 and remove H2 O2 by using Pd-Ru nanosheets (NSs) with the catalase (CAT)-like activity. More importantly, the finally produced O2 from H2 O2 decomposition can in turn facilitate the catalytic oxidation of UA, as the degradation of UA is an O2 consumption process. By integrating the high-efficiency enzymatic activity, long circulation capability, and good biocompatibility, the designed Pd-Ru/Uricase@RBC can effectively and safely treat hyperuricemia without side effects. The study affords a new alternative for the exploration of clinical treatment of hyperuricemia.

Estimating rotation angle from asymmetric projection of chest.

BACKGROUND: Manual or machine-based analysis of chest radiographs needs the images acquired with technical adequacy. Currently, the equidistance between the medial end of clavicles and the center of spinous processes serves as the only criterion to assess whether a frontal PA chest radiograph is taken with any rotation. However, this measurement is normally difficult to implement because there exists overlapping of anatomies within the region. Moreover, there is no way available to predict exact rotating angles even the distances were correctly measured from PA chest radiographs. OBJECTIVE: To quantitatively assess positioning adequacy of PA chest examination, this study proposes and investigates a new method to estimate rotation angles from asymmetric projection of thoracic cage on radiographs. METHOD: By looking into the process of radiographic projection, generalized expressions have been established to correlate rotating angles of thorax with projection difference of left and right sides of thoracic cage. A trunk phantom with different positioning angles is employed to acquire radiographs as standard reference to verify the theoretical expressions. RESULTS: The angles estimated from asymmetric projections of thoracic cage yield good agreement with those actual rotated angles, and an approximate linear relationship exists between rotation angle and asymmetric projection of thoracic cage. Under the experimental projection settings, every degree of rotation corresponds to the width difference of two sides of thoracic cage around 13-14 pixels. CONCLUSION: The proposed new method may be used to quantify rotating angles of chest and assess image quality for thoracic radiographic examination.

Discovery of a new chemical scaffold for the treatment of superbug Candida auris infections.

Candida auris has emerged as a serious threat of public health and caused global epidemic due to multi-drug resistance, remarkable transmissibility and high mortality. To tackle the challenging super fungus, novel benzoanilide antifungal agents were discovered by an integrated strategy of phenotypic screen, hit optimization, antifungal assays and mechanism exploration. The most promising compound A1 showed potent in vitro and in vivo efficacy against Candida auris infection. Mechanism investigation revealed that compound A1 blocked the biosynthesis of virulence factors and fungal cell walls through the inhibition of glycosylphosphatidylinositol (GPI) and GPI-anchored proteins. Thus, compound A1 represents a promising lead compound to combat drug-resistant candidiasis.

Correction: A self-activated cascade nanoreactor based on Pd-Ru/GOx for bacterial infection treatment.

Correction for 'A self-activated cascade nanoreactor based on Pd-Ru/GOx for bacterial infection treatment' by Tianbao Zhu et al., J. Mater. Chem. B, 2022, https://doi.org/10.1039/d2tb01416e.

A self-activated cascade nanoreactor based on Pd-Ru/GOx for bacterial infection treatment.

Enzyme cascade reactions that integrate natural enzymes and nanozymes have attracted intensive attention in biomedical studies. Nevertheless, it is still an important challenge to design simple, high-performance and safe cascade reaction systems. Herein, we constructed a cascade reactor Pd-Ru/GOx, in which two-dimensional Pd-Ru nanosheets (NSs) with excellent peroxidase (POD)-like activity were employed as a carrier for the covalent grafting of glucose oxidase (GOx) by glutaraldehyde coupling chemistry. The designed Pd-Ru/GOx cascade reactor possesses both GOx and POD-like activities and can not only transform non-toxic glucose into toxic hydroxyl radicals (˙OH) but also decrease the pH value of the reaction system to improve catalytic activity, achieving dual effects of cascade synergy and promotion. The in vitro and vivo experimental results manifested that Pd-Ru/GOx presented good antibacterial effects via the generation of reactive oxygen species (ROS). This work offers a simple strategy to construct a highly efficient and safe enzymatic cascade nanoreactor and holds tremendous promise for clinical bacterial infection control.

Preparation of Two-Dimensional Pd@Ir Nanosheets and Application in Bacterial Infection Treatment by the Generation of Reactive Oxygen Species.

Noble metal nanozymes have shown great promise in biomedicine; however, developing novel and high-performance noble metal nanozymes is still highly pressing and challenging. Herein, we, for the first time, prepared two-dimensional (2D) Pd@Ir bimetal nanosheets (NSs) with well-defined size and composition by a facile seed-mediated growth strategy. Enzyme-mimicked investigations find that the Pd@Ir NSs possess oxidase (OXD)-, peroxidase (POD)-, and catalase (CAT)-like multienzyme-mimetic activities. Especially, they exhibited much higher OXD- and POD-like activities than individual Pd NSs and Ir nanoparticles (NPs). The density functional theory (DFT) calculations reveal that the adsorption energy of O2 on Pd@Ir NSs is lower than that on the pure Pd NSs, which is more favorable for the conversion of O2 molecules from the triplet state (3O2) into the singlet state (1O2). Finally, based on the outstanding nanozyme activities to yield highly active singlet oxygen (1O2) and hydroxyl radicals (•OH) as well as excellent biosafety, the as-prepared Pd@Ir NSs were applied to treat bacteria-infected wounds, and satisfactory therapeutic outcomes were achieved. We believe that the highly efficient 2D Pd@Ir nanozyme will be an effective therapeutic reagent for various biomedical applications.

Non-small molecule PROTACs (NSM-PROTACs): Protein degradation kaleidoscope.

The proteolysis targeting chimeras (PROTACs) technology has been rapidly developed since its birth in 2001, attracting rapidly growing attention of scientific institutes and pharmaceutical companies. At present, a variety of small molecule PROTACs have entered the clinical trial. However, as small molecule PROTACs flourish, non-small molecule PROTACs (NSM-PROTACs) such as peptide PROTACs, nucleic acid PROTACs and antibody PROTACs have also advanced considerably over recent years, exhibiting the unique characters beyond the small molecule PROTACs. Here, we briefly introduce the types of NSM-PROTACs, describe the advantages of NSM-PROTACs, and summarize the development of NSM-PROTACs so far in detail. We hope this article could not only provide useful insights into NSM-PROTACs, but also expand the research interest of NSM-PROTACs.

Lanosterol 14α-demethylase (CYP51)/histone deacetylase (HDAC) dual inhibitors for treatment of Candida tropicalis and Cryptococcus neoformans infections.

Invasive fungal infections remain a challenge due to lack of effective antifungal agents and serious drug resistance. Discovery of antifungal agents with novel antifungal mechanism is important and urgent. Previously, we designed the first CYP51/HDAC dual inhibitors with potent activity against resistant Candida albicans infections. To better understand the antifungal spectrum and synergistic mechanism, herein new CYP51/HDAC dual inhibitors were designed which showed potent in vitro and in vivo antifungal activity against C. neoformans and C. tropicalis infections. Antifungal mechanism studies revealed that the CYP51/HDAC dual inhibitors acted by inhibiting various virulence factors of C. tropicalis and C. neoformans and down-regulating resistance-associated genes. This study highlights the potential of CYP51/HDAC dual inhibitors as a promising strategy for the discovery of novel broad-spectrum antifungal agents.

Near-Infrared Light Enhanced Peroxidase-Like Activity of PEGylated Palladium Nanozyme for Highly Efficient Biofilm Eradication.

The overall eradication of biofilm-mode growing bacteria holds significant key to the answer of a series of infection-related health problems. However, the extracellular matrix of bacteria biofilms disables the traditional antimicrobials and, more unfortunately, hampers the development of the anti-infectious alternatives. Therefore, highly effective antimicrobial agents are an urgent need for biofilm-infection control. Herein, a PEGylated palladium nanozyme (Pd-PEG) with peroxidase (POD)-like activity for highly efficient biofilm infection control is reported. Pd-PEG also shows the intrinsic photothermal effect as well as near-infrared (NIR) light-enhanced POD-like activity in the acidic environment, thereby massively destroying the biofilm matrix and killing the adhering bacteria. Importantly, the antimicrobial mechanism of the synergistic treatment based on Pd-PEG+H2O2+NIR combination was disclosed. In vitro and in vivo results illustrated the designed Pd-PEG+H2O2 +NIR treatment reagent possessed outstanding antibacterial and biofilms elimination effects with negligible biotoxicity. This work hopefully facilitates the development of metal-based nanozymes in biofilm related infectious diseases.

Pd@Pt-GOx/HA as a Novel Enzymatic Cascade Nanoreactor for High-Efficiency Starving-Enhanced Chemodynamic Cancer Therapy.

Glucose oxidase (GOx)-mediated starvation therapy has demonstrated good application prospect in cancer treatment. However, the glucose- and oxygen-depletion starvation therapy still suffers from some limitations like low therapeutic efficiency and potential side effects to normal tissues. To overcome these disadvantages, herein a novel enzymatic cascade nanoreactor (Pd@Pt-GOx/hyaluronic acid (HA)) with controllable enzymatic activities was developed for high-efficiency starving-enhanced chemodynamic cancer therapy. The Pd@Pt-GOx/HA was fabricated by covalent conjugation of GOx onto Pd@Pt nanosheets (NSs), followed by linkage with hyaluronic acid (HA). The modification of HA on Pd@Pt-GOx could block the GOx activity, catalase (CAT)-like and peroxidase (POD)-like activities of Pd@Pt, reduce the cytotoxicity to normal cells and organs, and effectively target CD44-overexpressed tumors by active targeting and passive enhanced permeability and retention (EPR) effect. After endocytosis by tumor cells, the intracellular hyaluronidase (Hyase) could decompose the outer HA and expose Pd@Pt-GOx for the enzymatic cascade reaction. The GOx on the Pd@Pt-GOx could catalyze the oxidation of intratumoral glucose by O2 for cancer starvation therapy, while the O2 produced from the decomposition of endogenous H2O2 by the Pd@Pt with the CAT-like activity could accelerate the O2-dependent depletion of glucose by GOx. Meanwhile, the upregulated acidity and H2O2 content in the tumor region generated by GOx catalytic oxidation of glucose dramatically facilitated the pH-responsive POD-like activity of the Pd@Pt nanozyme, which then catalyzed degradation of the H2O2 to generate abundant highly toxic •OH, thereby realizing nanozyme-mediated starving-enhanced chemodynamic cancer therapy. In vitro and in vivo results indicated that the controllable, self-activated enzymatic cascade nanoreactors exerted highly efficient anticancer effects with negligible biotoxicity.