MicroRNA-Triggered Programmable DNA-Encoded Pre-PROTACs for Cell-Selective and Controlled Protein Degradation.

Proteolysis-targeting chimeras (PROTACs) have accelerated drug development; however, some challenges still exist owing to their lack of tumor selectivity and on-demand protein degradation. Here, we developed a miRNA-initiated assembled pre-PROTAC (miRiaTAC) platform that enables the on-demand activation and termination of target degradation in a cell type-specific manner. Using miRNA-21 as a model, we engineered DNA hairpins labeled with JQ-1 and pomalidomide and facilitated the modular assembly of DNA-encoded pre-PROTACs through a hybridization chain reaction. This configuration promoted the selective polyubiquitination and degradation of BRD4 upon miR-21 initiation, highlighting significant tumor selectivity and minimal systemic toxicity. Furthermore, the platform incorporates photolabile groups, enabling the precise optical control of pre-PROTACs during DNA assembly/disassembly, mitigating the risk of excessive protein degradation. Additionally, by introducing a secondary ligand targeting CDK6, these pre-PROTACs were used as a modular scaffold for the programmable assembly of active miRiaTACs containing two different warheads in exact stoichiometry, enabling orthogonal multitarget degradation. The integration of near-infrared light-mediated photodynamic therapy through an upconversion nanosystem further enhanced the efficacy of the platform with potent in vivo anticancer activity. We anticipate that miRiaTAC represents a significant intersection between dynamic DNA nanotechnology and PROTAC, potentially expanding the versatility of PROTAC toolkit for cancer therapy.

Methanogenic Potential of Sewer Microbiomes and Its Implications for Methane Emission.

The sewer system, despite being a significant source of methane emissions, has often been overlooked in current greenhouse gas inventories due to the limited availability of quantitative data. Direct monitoring in sewers can be expensive or biased due to access limitations and internal heterogeneity of sewer networks. Fortunately, since methane is almost exclusively biogenic in sewers, we demonstrate in this study that the methanogenic potential can be estimated using known sewer microbiome data. By combining data mining techniques and bioinformatics databases, we developed the first data-driven method to analyze methanogenic potentials using a data set containing 633 observations of 53 variables obtained from literature mining. The methanogenic potential in the sewer sediment was around 250-870% higher than that in the wet biofilm on the pipe and sewage water. Additionally, k-means clustering and principal component analysis linked higher methane emission rates (9.72 ± 51.3 kgCO2 eq m-3 d-1) with smaller pipe size, higher water level, and higher potentials of sulfate reduction in the wetted pipe biofilm. These findings exhibit the possibility of connecting microbiome data with biogenic greenhouse gases, further offering insights into new approaches for understanding greenhouse gas emissions from understudied sources.

Nanozyme coating-gated multifunctional COF composite based dual-ratio enhanced dual-mode sensor for highly sensitive and reliable detection of organophosphorus pesticides in real samples.

The reliable detection of organophosphorus pesticides (OPs) in complex matrices remains an enormous challenge due to inevitable interference of sample matrices and testing factors. To address this issue, we designed a nanozyme-coated mesoporous COF with guest molecule loading, and successfully used it to construct a dual-ratio dual-mode sensor through target-regulated signal generation. The multifunctional COF-based composite (MB/COF@MnO2, MCM) featured high loading of methylene blue (MB), oxidase-like MnO2 coatings as gatekeepers, and specific recognition of thiocholine (TCh). TCh, a regulator produced from acetylcholinesterase (AChE)-catalyzed hydrolysis of acetylthiocholine, could decompose MnO2 coatings, triggering the release of abundant MB and oxidation of few o-phenylenediamine (OPD). OPs, strong inhibitors of AChE, could restrain TCh production and MnO2 decomposition, thereby controlling the release of less MB and oxidation of more OPD. This regulation boosted the dual-ratio dual-mode assay of OPs by using the released MB and oxidized OPD in the solution as testing signals, measured by both fluorescent and electrochemical methods. Experimental results demonstrated the sensitive detection of dichlorvos with LODs of 0.083 and 0.026 ng/mL via the fluorescent/electrochemical mode, respectively. This study represented a creative endeavor to develop dual-ratio dual-mode sensors for OPs detection in complex samples, offering high sensitivity, excellent selectivity, and good reliability.

Photo-triggered AuAg@g-C3N4 composite nanoplatform for multimodal broad-spectrum antibacterial therapy.

Strategies based on nanomaterials for sterilization address the problem of antibiotic resistance faced by conventional antimicrobials, with the contribution of photocatalytic compounds being particularly prominent. Herein, to integrate multiple bactericidal techniques into a system for generating synergistic antibacterial effects, a novel photo-triggered AuAg@g-C3N4 composite nanoplatform was constructed by anchoring AuAg on the surface of a g-C3N4 layer. As the composite nanoplatform had a lower bandgap and superior visible light utilization efficiency, it could facilitate free electron transfer better and exhibit superior photocatalytic activity under light conditions. Moreover, the AuAg@g-C3N4 composite nanoplatform integrated the bactericidal modes of silver ion toxicity, physical disruption of bacterial cell membranes by the multilayer structure, and excellent photocatalytic activity, exhibiting extremely superior bactericidal effects against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Bacillus subtilis, with a bactericidal efficiency of up to 100%.

Oxygen electrocatalysis-driven electrochemiluminescence by hierarchical carbon nanoflower-supported copper-modulated cobalt sulfide for cytosensing.

A facile cation modulation strategy is proposed for the synthesis of copper/cobalt bimetallic sulfides dispersed on hierarchical carbon nanoflowers, which exhibit excellent oxygen electrocatalysis capacity to drive electrochemiluminescence for cytosensing.

How local electric field regulates C-C coupling at a single nanocavity in electrocatalytic CO2 reduction.

C-C coupling is of utmost importance in the electrocatalytic reduction of CO2, as it governs the selectivity of diverse product formation. Nevertheless, the difficulties to directly observe C-C coupling pathways at a specific nanocavity hinder the advances in catalysts and electrolyzer design for efficient high-value hydrocarbon production. Here we develop a nano-confined Raman technology to elucidate the influence of the local electric field on the evolution of C-C coupling intermediates. Through precise adjustments to the Debye length in nanocavities of a copper catalyst, the overlapping of electrical double layers drives a transition in the C-C coupling pathway at a specific nanocavity from *CHO-*CO coupling to the direct dimerization of *CO species. Experimental evidence and simulations validate that a reduced potential drop across the compact layer promotes a higher yield of CO and promotes the direct dimerization of *CO species. Our findings provide insights for the development of highly selective catalyst materials tailored to promote specific products.

A "dual-key-and-lock" DNA nanodevice enables spatially controlled multimodal imaging and combined cancer therapy.

DNA-based theragnostic platforms have attracted more and more attention, while their applications are still impeded by nonspecific interference and insufficient therapeutic efficacy. Herein, we fabricate an integrated "dual-key-and-lock" DNA nanodevice (DKL-DND) which is composed of the inner Dox/Hairpin/Aptazyme-Au@Ag@Au probes and the outer metal-organic frameworks loaded with Fuel strand. Once internalized into human breast cancer cells (MCF-7), the DKL-DND is activated by cascaded endogenous stimuli (acidic pH in the lysosome and high expression of ATP in the cytoplasm), leading to spatially controlled optical/magnetic resonance multimodal imaging and gene/chemo/small molecule combined cancer therapy. By engineering pH and ATP-responsive units as cascaded locks on the DKL-DND, the operating status of the nanodevice and accessibility of encapsulated anti-tumour drugs can be precisely regulated in the specified physiological states, avoiding the premature activation and release during assembly and delivery. Both in vitro and in vivo assessments demonstrate that the DKL-DND with excellent stimuli-responsive ability, biocompatibility, stability and accumulation behaviour was capable of simultaneously affording accurate tumour diagnosis and efficient tumour growth inhibition. This integrated DKL-DND exhibits great promise in constructing self-adaptive nanodevices for multimodal imaging-guided combination therapy.

Multi-Shell Nanourchin-Integrated Dual Mode Lateral Flow Immunoassay for Sensitive and Rapid Detection of Clinical Cardiac Myosin-Binding Protein C.

Cardiac myosin-binding protein C (cMyBP-C) is a novel cardiac marker of acute myocardial infarction (AMI) and acute cardiac injuries (ACI). Construction of point-of-care testing techniques capable of sensing cMyBP-C with high sensitivity and precision is urgently needed. Herein, we synthesized an Au@NGQDs@Au/Ag multi-shell nanoUrchins (MSNUs), and then applied it in a colorimetric/SERS dual-mode immunoassay for detection of cMyBP-C. The MSNUs displayed superior stability, colorimetric brightness, and SERS enhancement ability with an enhanced factor of 5.4 × 109, which were beneficial to improve the detection capability of test strips. The developed MSNU-based test strips can achieve an ultrasensitive immunochromatographic assay of cMyBP-C in both colorimetric and SERS modes with the limits of detection as low as 19.3 and 0.77 pg/mL, respectively. Strikingly, this strip was successfully applied to analyze actual plasma samples with significantly better sensitivity, negative predictive value, and accuracy than commercially available gold test strips. Notably, this method possessed a wide range of application scenarios via combining with a color recognizer application named Color Grab on the smartphone, which can meet various needs of different users. Overall, our MSNU-based test strip as a mobile health monitoring tool shows excellent sensitivity, reproducibility, and rapid detection of the cMyBP-C, which holds great potential for the early clinic diagnosis of AMI and ACI.

Self-Regenerating Photothermal Agents for Tandem Photothermal and Thermodynamic Tumor Therapy.

Small molecule-based photothermal agents (PTAs) hold promising future for photothermal therapy; however, unexpected inactivation exerts negative impacts on their application clinically. Herein, a self-regenerating PTA strategy is proposed by integrating 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation (ABTS•+) with a thermodynamic agent (TDA) 2,2'-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPH). Under NIR laser, the photothermal effect of ABTS•+ accelerates the production of alkyl radicals by AIPH, which activates the regeneration of ABTS•+, thus creating a continuous positive feedback loop between photothermal and thermodynamic effects. The combination of ABTS•+ regeneration and alkyl radical production leads to the tandem photothermal and thermodynamic tumor therapy. In vitro and in vivo experiments confirm that the synergistic action of thermal ablation, radical damage, and oxidative stress effectively realizes tumor suppression. This work offers a promising approach to address the unwanted inactivation of PTAs and provides valuable insights for optimizing combination therapy.

A photoactivatable upconverting nanodevice boosts the lysosomal escape of PROTAC degraders for enhanced combination therapy.

PROteolysis TArgeting Chimeras have received increasing attention due to their capability to induce potent degradation of various disease-related proteins. However, the effective and controlled cytosolic delivery of current small-molecule PROTACs remains a challenge, primarily due to their intrinsic shortcomings, including unfavorable solubility, poor cell permeability, and limited spatiotemporal precision. Here, we develop a near-infrared light-controlled PROTAC delivery device (abbreviated as USDPR) that allows the efficient photoactivation of PROTAC function to achieve enhanced protein degradation. The nanodevice is constructed by encapsulating the commercial BRD4-targeting PROTACs (dBET6) in the hollow cavity of mesoporous silica-coated upconversion nanoparticles, followed by coating a Rose Bengal (RB) photosensitizer conjugated poly-L-lysine (PLL-RB). This composition enables NIR light-activatable generation of cytotoxic reactive oxygen species due to the energy transfer from the UCNPs to PLL-RB, which boosts the endo/lysosomal escape and subsequent cytosolic release of dBET6. We demonstrate that USDPR is capable of effectively degrading BRD4 in a NIR light-controlled manner. This in combination with NIR light-triggered photodynamic therapy enables an enhanced antitumor effect both in vitro and in vivo. This work thus presents a versatile strategy for controlled release of PROTACs and codelivery with photosensitizers using an NIR-responsive nanodevice, providing important insight into the design of effective PROTAC-based combination therapy.

Bioinspired molecule-functionalized Cu with high CO adsorption for efficient CO electroreduction to acetate.

Electrochemical reduction of carbon dioxide (CO2) or carbon monoxide (CO) to valuable multi-carbon (C2+) products like acetate is a promising approach for a sustainable energy economy. However, it is still challenging to achieve high activity and selectivity for acetate production, especially in neutral electrolytes. Herein, a bioinspired hemin/Cu hybrid catalyst was developed to enhance the surface *CO coverage for highly efficient electroreduction of CO to acetate fuels. The hemin/Cu electrocatalyst exhibits a remarkable faradaic efficiency of 45.2% for CO-to-acetate electroreduction and a high acetate partial current density of 152.3 mA cm-2. Furthermore, the developed hybrid catalyst can operate stably at 200 mA cm-2 for 14.6 hours, producing concentrated acetate aqueous solutions (0.235 M, 2.1 wt%). The results of in situ Raman spectroscopy and theoretical calculations proved that the Fe-N4 structure of hemin could enhance the CO adsorption and enrich the local concentration of CO, thereby improving C-C coupling for acetate production. In addition, compared to the unmodified Cu catalysts, the Cu catalysts functionalized with cobalt phthalocyanine with a Co-N4 structure also exhibit improved acetate performance, proving the universality of this bioinspired molecule-enhanced strategy. This work paves a new way to designing bioinspired electrolysis systems for producing specific C2+ products from CO2 or CO electroreduction.

Machine Learning for Polymer Design to Enhance Pervaporation-Based Organic Recovery.

Pervaporation (PV) is an effective membrane separation process for organic dehydration, recovery, and upgrading. However, it is crucial to improve membrane materials beyond the current permeability-selectivity trade-off. In this research, we introduce machine learning (ML) models to identify high-potential polymers, greatly improving the efficiency and reducing cost compared to conventional trial-and-error approach. We utilized the largest PV data set to date and incorporated polymer fingerprints and features, including membrane structure, operating conditions, and solute properties. Dimensionality reduction, missing data treatment, seed randomness, and data leakage management were employed to ensure model robustness. The optimized LightGBM models achieved RMSE of 0.447 and 0.360 for separation factor and total flux, respectively (logarithmic scale). Screening approximately 1 million hypothetical polymers with ML models resulted in identifying polymers with a predicted permeation separation index >30 and synthetic accessibility score <3.7 for acetic acid extraction. This study demonstrates the promise of ML to accelerate tailored membrane designs.

Operando Spectroscopic Elucidation of the Bubble Sunshade Effect in Inorganic-Biological Hybrids for Photosynthetic Hydrogen Production.

Hydrogen production by photosynthetic hybrid systems (PBSs) offers a promising avenue for renewable energy. However, the light-harvesting efficiency of PBSs remains constrained due to unclear intracellular kinetic factors. Here, we present an operando elucidation of the sluggish light-harvesting behavior for existing PBSs and strategies to circumvent them. By quantifying the spectral shift in the structural color scattering of individual PBSs during the photosynthetic process, we observe the accumulation of product hydrogen bubbles on their outer membrane. These bubbles act as a sunshade and inhibit light absorption. This phenomenon elucidates the intrinsic constraints on the light-harvesting efficiency of PBSs. The introduction of a tension eliminator into the PBSs effectively improves the bubble sunshade effect and results in a 4.5-fold increase in the light-harvesting efficiency. This work provides valuable insights into the dynamics of transmembrane transport gas products and holds the potential to inspire innovative designs for improving the light-harvesting efficiency of PBSs.

DNA Walker-Driven Mass Nanotag Assembly System for Simultaneously Profiling Dual Markers of Oxidative Stress at Different Cellular Locations.

Simultaneous profiling of redox-regulated markers at different cellular sublocations is of great significance for unraveling the upstream and downstream molecular mechanisms of oxidative stress in living cells. Herein, by synchronizing dual target-triggered DNA machineries in one nanoentity, we engineered a DNA walker-driven mass nanotag (MNT) assembly system (w-MNT-AS) that can be sequentially activated by oxidative stress-associated mucin 1 (MUC1) and apurinic/apyrimidinic endonuclease 1 (APE1) from plasma membrane to cytoplasm and induce recycled assembly of MNTs for multiplex detection of the two markers by matrix-assisted laser desorption ionization mass spectrometry (MALDI MS). In the working cascade, the sensing process governs the separate activation of w-MNT-AS by MUC1 and APE1 in diverse locations, while the assembly process contributes to the parallel amplification of the ion signal of the characteristic mass tags. In this manner, the differences between MCF-7, HeLa, HepG2, and L02 cells in membrane MUC1 expression and cytoplasmic APE1 activation were fully characterized. Furthermore, the oxidative stress level and dynamics caused by exogenous H2O2, doxorubicin, and simvastatin were comprehensively demonstrated by tracking the fate of the two markers across different cellular locations. The proposed w-MNT-AS coupled MS method provides an effective route to probe multiple functional molecules that lie at different locations while participating in the same cellular event, facilitating the mechanistic studies on cellular response to oxidative stress and other disease-related cellular processes.

Versatile Metal-Organic Framework Incorporating Ag2S for Constructing a Photoelectrochemical Immunosensor for Two Breast Cancer Markers.

Breast cancer poses the significance of early diagnosis and treatment. Here, we developed an innovative photoelectrochemical (PEC) immunosensor characterized by high-level dual photocurrent signals and exceptional sensitivity. The PEC sensor, denoted as MIL&Ag2S, was constructed by incorporating Ag2S into a metal-organic framework of MIL-101(Cr). This composite not only enhanced electron-hole separation and conductivity but also yielded robust and stable dual photocurrent signals. Through the implementation of signal switching, we achieved the combined detection of cancer antigen 15-3 (CA15-3) and carcinoembryonic antigen (CEA) with outstanding stability, reproducibility, and specificity. The results revealed a linear range for CEA detection spanning 0.01-32 ng/mL, with a remarkably low detection limit of 0.0023 ng/mL. Similarly, for CA15-3 detection, the linear range extended from 0.1 to 320 U/mL, with a low detection limit of 0.014 U/mL. The proposed strategy introduces new avenues for the development of highly efficient, cost-effective, and user-friendly PEC sensors. Furthermore, it holds promising prospects for early clinical diagnosis, contributing to potential breakthroughs in medical detection and ultimately improving patient outcomes.

Ring-Contracted Artemisinin Derivatives as Novel CDK 4/6 Inhibitors: Synthesis and Anti-Breast Cancer Evaluation.

The endoperoxide group of artemisinins is universally accepted an essential group for their anti-cancer effects. In this study, a series of D-ring-contracted artemisinin derivatives were constructed by combining ring-contracted artemisinin core with fragments of functional heterocyclic molecules or classical CDK4/6 inhibitors to identify more efficacious breast cancer treatment agents. Twenty-six novel hybridized molecules were synthesized and characterized by HRMS, IR, 1H-NMR and 13C NMR. In antiproliferative activities and kinase inhibitory effects assays, we found that the antiproliferative effects of B01 were close to those of the positive control Palbociclib, with GI50 values of 4.87±0.23 µM and 9.97±1.44 µM towards T47D cells and MDA-MB-436 cells respectively. In addition, the results showed that B01 was the most potent compound against CDK6/cyclin D3 kinase, with an IC50 value of 0.135±0.041 µM, and its activity was approximately 1/3 of the positive control Palbociclib.

High Dynamic Range Probing of Single-Molecule Mechanical Force Transitions at Cell-Matrix Adhesion Bonds by a Plasmonic Tension Nanosensor.

Mechanical signals in animal tissues are complex and rapidly changed, and how the force transduction emerges from the single-cell adhesion bonds remains unclear. DNA-based molecular tension sensors (MTS), albeit successful in cellular force probing, were restricted by their detection range and temporal resolution. Here, we introduced a plasmonic tension nanosensor (PTNS) to make straight progress toward these shortcomings. Contrary to the fluorescence-based MTS that only has specific force response thresholds, PTNS enabled the continuous and reversible force measurement from 1.1 to 48 pN with millisecond temporal resolution. We used the PTNS to visualize the high dynamic range single-molecule force transitions at cell-matrix adhesions during adhesion formation and migration. Time-resolved force traces revealed that the lifetime and duration of stepwise force transitions of molecular clutches are strongly modulated by the traction force through filamentous actin. The force probing technique is sensitive, fast, and robust and constitutes a potential tool for single-molecule and single-cell biophysics.

Autocrine phosphatase PDP2 inhibits ferroptosis by dephosphorylating ACSL4 in the Luminal A Breast Cancer.

Phosphatases can dephosphorylate phosphorylated kinases, leading to their inactivation, and ferroptosis is a type of cell death. Therefore, our aim is to identify phosphatases associated with ferroptosis by analyzing the differentially expressed genes (DEGs) of the Luminal A Breast Cancer (LumABC) cohort from the Cancer Genome Atlas (TCGA). An analysis of 260 phosphatase genes from the GeneCard database revealed that out of the 28 DEGs with high expression, only the expression of pyruvate dehydrogenase phosphatase 2 (PDP2) had a significant correlation with patient survival. In addition, an analysis of DEGs using gene ontology, Kyoto Encyclopedia of Genes and Genomes and gene set enrichment analysis revealed a significant variation in the expression of ferroptosis-related genes. To further investigate this, we analyzed 34 ferroptosis-related genes from the TCGA-LumABC cohort. The expression of long-chain acyl-CoA synthetase 4 (ACSL4) was found to have the highest correlation with the expression of PDP2, and its expression was also inversely proportional to the survival rate of patients. Western blot experiments using the MCF-7 cell line showed that the phosphorylation level of ACSL4 was significantly lower in cells transfected with the HA-PDP2 plasmid, and ferroptosis was correspondingly reduced (p < 0.001), as indicated by data from flow cytometry detection of membrane-permeability cell death stained with 7-aminoactinomycin, lipid peroxidation, and Fe2+. Immunoprecipitation experiments further revealed that the phosphorylation level of ACSL4 was only significantly reduced in cells where PDP2 and ACSL4 co-precipitated. These findings suggest that PDP2 may act as a phosphatase to dephosphorylate and inhibit the activity of ACSL4, which had been phosphorylated and activated in LumABC cells. Further experiments are needed to confirm the molecular mechanism of PDP2 inhibiting ferroptosis.

Lipid concentration and composition in xylem sap of woody angiosperms from a tropical savanna and a seasonal rainforest.

Lipids may play an important role in preventing gas embolisms by coating nanobubbles in xylem sap. Few studies on xylem sap lipids have been reported for temperate plants, and it remain unclear whether sap lipids have adaptational significance in tropical plants. In this study, we quantify the lipid composition of xylem sap for angiosperm species from a tropical savanna (seven species) and a seasonal rainforest (five species) using mass spectrometry. We found that all twelve species studied contained lipids in their xylem sap, including galactolipids, phospholipids and triacylglycerol, with a total lipid concentration ranging from 0.09 to 0.26 nmol/L. There was no difference in lipid concentration or composition between plants from the two sites, and the lipid concentration was negatively related to species' open vessel volume. Furthermore, savanna species showed little variation in lipid composition between the dry and the rainy season. These results support the hypothesis that xylem sap lipids are derived from the cytoplasm of individual conduit cells, remain trapped inside individual conduits, and undergo few changes in composition over consecutive seasons. A xylem sap lipidomic data set, which includes 12 tropical tree species from this study and 11 temperate tree species from literature, revealed no phylogenetic signals in lipid composition for these species. This study fills a knowledge gap in the lipid content of xylem sap in tropical trees and provides additional support for their common distribution in xylem sap of woody angiosperms. It appears that xylem sap lipids have no adaptive significance.

Quantifying source contributions to ambient NH3 using Geo-AI with time lag and parcel tracking functions.

Ambient ammonia (NH3) plays an important compound in forming particulate matters (PMs), and therefore, it is crucial to comprehend NH3's properties in order to better reduce PMs. However, it is not easy to achieve this goal due to the limited range/real-time NH3 data monitored by the air quality stations. While there were other studies to predict NH3 and its source apportionment, this manuscript provides a novel method (i.e., GEO-AI)) to look into NH3 predictions and their contribution sources. This study represents a pioneering effort in the application of a novel geospatial-artificial intelligence (Geo-AI) base model with parcel tracking functions. This innovative approach seamlessly integrates various machine learning algorithms and geographic predictor variables to estimate NH3 concentrations, marking the first instance of such a comprehensive methodology. The Shapley additive explanation (SHAP) was used to further analyze source contribution of NH3 with domain knowledge. From 2016 to 2018, Taichung's hourly average NH3 values were predicted with total variance up to 96%. SHAP values revealed that waterbody, traffic and agriculture emissions were the most significant factors to affect NH3 concentrations in Taichung among all the characteristics. Our methodology is a vital first step for shaping future policies and regulations and is adaptable to regions with limited monitoring sites.