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The ten-eleven translocation (TET) family of dioxygenases maintain stable local DNA demethylation during cell division and lineage specification. As the major catalytic product of TET enzymes, 5-hydroxymethylcytosine is selectively enriched at specific genomic regions, such as enhancers, in a tissue-dependent manner. However, the mechanisms underlying this selectivity remain unresolved. Here we unveil a low-complexity insert domain within TET2 that facilitates its biomolecular condensation with epigenetic modulators, such as UTX and MLL4. This co-condensation fosters a permissive chromatin environment for precise DNA demethylation. Disrupting low-complexity insert-mediated condensation alters the genomic binding of TET2 to cause promiscuous DNA demethylation and genome reorganization. These changes influence the expression of key genes implicated in leukaemogenesis to curtail leukaemia cell proliferation. Collectively, this study establishes the pivotal role of TET2 condensation in orchestrating precise DNA demethylation and gene transcription to support tumour cell growth.

Rational design and construction of advanced sensing platforms for sensitive detection of H2O2released from living cells is one of the challenges in the field of physiology and pathology. Noble metal clusters are a kind of nanomaterials with well-defined chemical composition and special atomic structures, which have been widely explored in catalysis, biosensing, and therapy. Compared with noble metal nanoparticles, noble metal clusters exhibit great potential in electrochemical biosensing due to their high atom utilization efficiency and abundant reactive active sites. Herein, Pt nanoclusters anchored on hollow carbon spheres (PtNCS/HCS) were successfully prepared for sensitive detection of H2O2. By tuning the ratio of Pt(0)/Pt(II) at different annealing temperatures, the optimized PtNCS/HCS-550 showed higher H2O2reduction and oxidation catalytic activities than other control samples. Density functional theory calculations revealed that H2O2*can be better activated and dissociated in the Pt0IImodel featured with the co-existence of Pt(0)/Pt(II) and the key intermediates OOH*/OH* have a stronger interaction with the Pt0IImodel. As a concept application, the electrochemical biosensing platform was successfully applied to sensitive detection of H2O2released from the cells.

Inspired by the key role of the coordination environment in the catalytic activity of enzymes, a rational design of the coordination structure of active sites at the atom scale is expected to develop high-performance enzyme-like catalysts. Here, we design a simple model system involving pentacoordinated and tetracoordinated Fe–N–C single-atom catalysts (named NG-Heme and G-Heme, respectively) to investigate structure–activity relationships. NG-Heme with axial ligand-engineered Fe sites exhibits superior enzyme-like activity to G-Heme, achieving the goal of vivid mimicking of the active sites of peroxidase. Experiments and theoretical studies reveal that the enhanced intrinsic catalytic activity originates from the “push effect” of the additional axial ligand, which can strengthen the interaction between the active site and the intermediate. Based on the outstanding catalytic activity, an NG-Heme-linked immunosorbent assay was constructed for colorimetric detection of carcinoembryonic antigen, exhibiting satisfactory sensitivity and feasibility in the analysis of clinical samples.

The tight regulation of intracellular nucleotides is critical for the self-renewal and lineage specification of hematopoietic stem cells (HSCs). Nucleosides are major metabolite precursors for nucleotide biosynthesis and their availability in HSCs is dependent on their transport through specific membrane transporters. However, the role of nucleoside transporters in the differentiation of HSCs to the erythroid lineage and in red cell biology remains to be fully defined. Here, we show that the absence of the equilibrative nucleoside transporter (ENT1) in human red blood cells with a rare Augustine-null blood type is associated with macrocytosis, anisopoikilocytosis, an abnormal nucleotide metabolome, and deregulated protein phosphorylation. A specific role for ENT1 in human erythropoiesis was demonstrated by a defective erythropoiesis of human CD34+progenitors following short hairpin RNA-mediated knockdown of ENT1. Furthermore, genetic deletion of ENT1 in mice was associated with reduced erythroid progenitors in the bone marrow, anemia, and macrocytosis. Mechanistically, we found that ENT1-mediated adenosine transport is critical for cyclic adenosine monophosphate homeostasis and the regulation of erythroid transcription factors. Notably, genetic investigation of 2 ENT1nullindividuals demonstrated a compensation by a loss-of-function variant in the ABCC4cyclic nucleotide exporter. Indeed, pharmacological inhibition of ABCC4 in Ent1−/−mice rescued erythropoiesis. Overall, our results highlight the importance of ENT1-mediated nucleotide metabolism in erythropoiesis.

The tight regulation of intracellular nucleotides is critical for the self-renewal and lineage specification of hematopoietic stem cells (HSCs). Nucleosides are major metabolite precursors for nucleotide biosynthesis and their availability in HSCs is dependent on their transport through specific membrane transporters. However, the role of nucleoside transporters in the differentiation of HSCs to the erythroid lineage and in red cell biology remains to be fully defined. Here, we show that the absence of the equilibrative nucleoside transporter (ENT1) in human red blood cells with a rare Augustine-null blood type is associated with macrocytosis, anisopoikilocytosis, an abnormal nucleotide metabolome, and deregulated protein phosphorylation. A specific role for ENT1 in human erythropoiesis was demonstrated by a defective erythropoiesis of human CD34+ progenitors following short hairpin RNA-mediated knockdown of ENT1. Furthermore, genetic deletion of ENT1 in mice was associated with reduced erythroid progenitors in the bone marrow, anemia, and macrocytosis. Mechanistically, we found that ENT1-mediated adenosine transport is critical for cyclic adenosine monophosphate homeostasis and the regulation of erythroid transcription factors. Notably, genetic investigation of 2 ENT1null individuals demonstrated a compensation by a loss-of-function variant in the ABCC4 cyclic nucleotide exporter. Indeed, pharmacological inhibition of ABCC4 in Ent1−/− mice rescued erythropoiesis. Overall, our results highlight the importance of ENT1-mediated nucleotide metabolism in erythropoiesis.

Reactive oxygen species (ROS)‐involved tumor therapeutic strategy, chemodynamic therapy (CDT), has attracted extensive research interest in the scientific community. However, the therapeutic effect of CDT is insufficient and unsustainable owing to the limited endogenous H2O2level in the tumor microenvironment. Here, peroxidase (POD)‐like RuTe2nanozyme with the immobilization of glucose oxidase (GOx) and allochroic 3,3′,5,5′‐tetramethylbenzidine (TMB) molecule have been synthesized to construct RuTe2‐GOx‐TMB nanoreactors (RGT NRs) as cascade reaction systems for tumor‐specific and self‐replenishing cancer therapy. GOx in sequential nanocatalysts can effectively deplete glucose in tumor cells. Meanwhile, a sustainable supply of H2O2for subsequent Fenton‐like reactions catalyzed by RuTe2nanozyme is achieved in response to the mild acidic tumor microenvironment. Through this cascade reaction, highly toxic hydroxyl radicals (·OH) are produced, which can further oxidize TMB to trigger tumor‐specific “turn‐on” photothermal therapy (PTT). In addition, PTT and massive ROS can stimulate the tumor immune microenvironment and activate the systematic anti‐tumor immune responses, exerting a notable effect on hindering tumor recurrence and metastasis. This study paves a promising paradigm for synergistic starvation therapy, PTT, and CDT cancer therapy with high efficiency. A cascaded “all‐in‐one” platform is constructed for tumor‐specific starvation‐/chemodynamic‐/ photothermal therapy based on RuTe2nanorods. The loaded glucose oxidase not only effectively depletes glucose in tumor cells and sustainable supply of H2O2for amplified therapeutic efficiency but also triggers “turn‐on” photothermal therapy. This study paves a promising paradigm for tumor‐specific synergistic therapy.

Here, we demonstrated a pH-responsive nanocluster based on ZnO quantum dots (QDs) and investigated its potential in drug delivery with tumor-specific accumulation. The nanoclusters were composed of small single ZnO QDs by cross-linking dicarboxyl-terminated poly(ethylene glycol) (PEG), showing high stability and biocompatibility in physiological fluids. The clustered ZnO QDs were capable of loading a large quantity of doxorubicin (DOX) via complexation and covalent interactions. After cellular uptake, the drug was efficiently released because the carrier was completely dissolved; the metal-drug complex was disassembled in response to decreasing pH in the endosomes within tumor cells. Moreover, the viability of cancer cells was significantly decreased because the ZnO QDs exhibited cytotoxicity postdissolution and preferentially killed cancerous cells compared to normal cells. Furthermore, this pH-responsive PEG-cZnO QDs cluster system may be capable of tumor homing while circulating in the blood via the enhanced permeability and retention (EPR) effect.

In this paper, we reported a ZnO quantum dots-based pH-responsive drug delivery platform for intracellular controlled release of drugs. Acid-decomposable, luminescent aminated ZnO quantum dots (QDs) were synthesized as nanocarriers with ultrasmall size (∼3 nm). The dicarboxyl-terminated poly(ethylene glycol) (PEG) had been introduced to NH2–ZnO QDs, which rendered it stable under physiological fluid. Moreover, a targeting ligand, hyaluronic acid (HA), was conjugated to ZnO QDs for specifically binding to the overexpressed glycoprotein CD44 by cancer cells. Doxorubicin (DOX) molecules were successfully loaded to PEG functionalized ZnO QDs via formation of metal–DOX complex and covalent interactions. The pH-sensitive ZnO QDs dissolved to Zn2+in acidic endosome/lysosome after uptake by cancer cells, which triggered dissociation of the metal–drug complex and a controlled DOX release. As result, a synergistic therapy was achieved due to incorporation of the antitumor effect of Zn2+and DOX.

Five Chinese herbal medicinesmatrine, oxymatrine, sophoridine, artemisinin, and dihydroartemisininwere investigated using vibrational circular dichroism (VCD) experiments and density functional theory calculations to extract their stereochemical information. The three matrine-type alkaloids are available from the dry roots of Sophora flavescensand have long been used in various traditional Chinese herbal medicines to combat diseases such as cancer and cardiac arrhythmia. Artemisinin and the related dihydroartemisinin, discovered in 1979 by Professor Youyou Tu, a 2015 Nobel laureate in medicine, are effective drugs for the treatment of malaria. The VCD measurements were carried out in CDCl3and DMSO-d6, two solvents with different dielectric constants and hydrogen-bonding characteristics. A “clusters-in-a-liquid” approach was used to model both explicit and implicit solvent effects. The studies show that effectively accounting for solvent effects is critical to using IR and VCD spectroscopy to provide unique spectroscopic features to differentiate the potential stereoisomers of these Chinese herbal medicines.

Considering the urgent need to explore multifunctional drug delivery system for overcoming multidrug resistance, we prepared a new nanocarbon material Q-Graphene as a nanocarrier for killing drug-resistant lung cancer cells. Attributing to the introduction of hyaluronic acid and rhodamine B isothiocyanate (RBITC), the Q-Graphene-based drug delivery system was endowed with dual function of targeted drug delivery and fluorescence imaging. Additionally, doxorubicin (DOX) as a model drug was loaded on the surface of Q-Graphene via π–π stacking. Interestingly, the fluorescence of DOX was quenched by Q-Graphene due to its strong electron-accepting capability, and a significant recovery of fluorescence was observed, while DOX was released from Q-Graphene. Because of the RBITC labeling and the effect of fluorescence quenching/restoring of Q-Graphene, the uptake of nanoparticles and intracellular DOX release can be tracked. Overall, a highly promising multifunctional nanoplatform was developed for tracking and monitoring targeted drug delivery for efficiently killing drug-resistant cancer cells.

Based on førster resonance energy transfer, the nanoantenna containing over 4000 donor dyes can achieve unprecedented signal amplification and biosensing sensitivity.With light irradiation, the light-harvesting nanoantenna effectively disrupted lysosomal structures by generation of reactive oxygen species, substantially achieved cytosol delivery.The zeptomolar sensitivity of nanoantenna provides accurate bioimaging of miR-210 in multiple cell lines and in vivo assay, which creates a pathway for the creation of miRNA toolbox for quantitative epigenetics and personalized medicine.

Enzyme immobilization plays an essential role in solving the problems of the inherently fragile nature of enzymes. Although prominent stability and reuse of enzymes can be achieved by enzyme immobilization, their bioactivity and catalytic efficiency will be adversely affected. Herein, PdCu hydrogel nanozymes with a hierarchically porous structure were used to immobilize horseradish peroxidase (HRP) to obtain PdCu@HRP. In addition to the improvement of stability and reusability, PdCu@HRP displayed synergistically enhanced activities than native HRP and PdCu hydrogels. Not only the specific interactions between PdCu hydrogel nanozymes and enzymes but also the enrichment of substrates around enzymes by electrostatic adsorption of hydrogels was proposed to expound the enhanced catalytic activity. Accordingly, by taking advantage of the excellent catalytic performance of the PdCu@HRP and the glucose oxidase encapsulated in zeolitic imidazolate framework-8, colorimetric biosensing of the carcinoembryonic antigen via catalytic cascade reactions for achieving signal amplification was performed. The obtained biosensor enhanced the detection sensitivity by approximately 6.1-fold as compared to the conventional HRP-based enzyme-linked immunosorbent assay, demonstrating the promising potential in clinical diagnosis.

Benefiting from the maximum atom-utilization efficiency and distinct structural features, single-atom catalysts open a new avenue for the design of more functional catalysts, whereas their bioapplications are still in their infancy. Due to the advantages, platinum single atoms supported by cadmium sulfide nanorods (Pt SAs-CdS) are synthesized to build an ultrasensitive photoelectrochemical (PEC) biosensing platform. With the decoration of Pt SAs, the PEC signal of CdS is significantly boosted. Furthermore, theory calculations indicate the positively charged Pt SAs could change the charge distribution and increase the excited carrier density of CdS. Meanwhile, it also suggests that Cu2+can severely hinder the photoexcitation and electron–hole separation of CdS. As a proof of concept, prostate-specific antigen is chosen as the target analyte to demonstrate the superiority of the Pt SAs-CdS-based PEC sensing system. As a result, the PEC biosensor based on Pt SAs-CdS exhibits outstanding detection sensitivity and promising applicability.

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