ASAP (As Soon As Publishable)

The chemoselective incorporation of arginine carbonylation post-translational modification (PTM) within proteins represents an underexplored frontier. This is largely due to the poor nucleophilicity and resistance to chemical oxidation of arginine. Drawing inspiration from the metal catalyzed oxidation (MCO) processes of arginine, we introduce a chemical methodology aimed at generating glutamate-5-semialdehyde from arginine residues within peptides and proteins. This innovative chemical approach capitalizes on the inherent weak nucleophilicity and oxidative properties of arginine. We also demonstrate the application of this strategy to selectively introduce both natural and unnatural post-translational modifications (PTMs) in a targeted manner. Our chemical approach offers a rapid, robust, and highly selective technique, facilitating chemoproteomic profiling of arginine sites prone to forming glutamate-5-semialdehyde PTM within the human proteome. Additionally, this methodology serves as a versatile platform for uncovering microenvironments that are susceptible to undergoing arginine carbonylation PTM, enabling the understanding of the effect of oxidative stress on arginine in proteins and the impact of these PTMs on cellular processes.

Regioselective carbohydroxylation and aminohydroxylation of α-olefins were developed by a photoredox catalyst and pyridine N-oxide. This approach offers the catalytic and direct conversion of unactivated alkenes to a series of primary alcohols, including those bearing β-quaternary carbon centers and β-amino alcohols. The regioselective difunctionalization is enabled by the radical addition of α-olefin from the pyridine N-oxy radical, which is generated from readily available pyridine N-oxide via photoredox catalyzed single-electron oxidation. A combination of experimental and computational mechanistic studies was employed to lend support for the proposed reaction mechanism that proceeds via interwoven radical steps and polar substitution. The implications of this method for regioselective difunctionalization of α-olefins were further demonstrated by the examples of carboetherification, carboesterification, and lactone formation.

Determining hydrogen positions in metal hydride clusters remains a formidable challenge, which relies heavily on unaffordable neutron diffraction. While machine learning has shown promise, only one deep learning-based method has been proposed so far, which relies heavily on neutron diffraction data for training, limiting its general applicability. In this work, we present an innovative strategy─SSW-NN (stochastic surface walking with neural network)─a robust, non-neutron diffraction-dependent technique that accurately predicts hydrogen positions. Validated against neutron diffraction data for copper hydride clusters, SSW-NN proved effective for clusters where only X-ray diffraction data or DFT predictions are available. It offers superior accuracy, efficiency, and versatility across different metal hydrides, including silver and alloy hydride systems, currently without any neutron diffraction references. This approach not only establishes a new research paradigm for metal hydride clusters but also provides a universal solution for hydrogen localization in other research fields constrained by neutron sources.

The M₂ muscarinic receptor (M₂R) is a prototypical G protein-coupled receptor (GPCR) that serves as a model system for understanding ligand recognition and GPCR activation. Here, using vibrational spectroscopy, we identify the mechanisms governing M₂R activation by its native agonist, acetylcholine. Combined with mutagenesis, computational chemistry, and organic synthetic chemistry, our analyses found that the precise distance between acetylcholine and Asn404, one of the amino acids constituting the ligand-binding site, is important for M₂R activation and that the N404Q mutant undergoes partial active state-like conformational changes. We discovered that a water molecule bridging acetylcholine and Asn404 forms a precise and flexible hydrogen bond network, triggering the outward movement of transmembrane helix 6 in M₂R. Consistent with this observation, disruptions in this hydrogen bond network via chemical modification at the α- or β-position of acetylcholine failed to activate M₂R. Collectively, our findings pinpoint Asn404 as a critical residue that both senses acetylcholine binding and induces M₂R activation.

Commodity plastics such as high density polyethylene (HDPE) have become integral to society. However, the potentially long-lasting ecological impacts of these plastics have spurred researchers to search for more sustainable solutions. One such solution is to develop a method for designing plastics with tunable and improved properties, thus decreasing the amount of material needed for various applications. In this work, we report a machine learning approach that maps the relationship between polymer molecular weight distributions (MWDs) and the physical properties (tensile and rheological) of HDPE. Using this approach, we design and generate HDPE materials with user-specified properties and valorize degraded postconsumer polyethylene waste. Implementation and development of this approach will facilitate the design of next-generation commodity materials and enable more efficient polymer recycling, thereby lowering the overall impact of HDPE on the environment.

Green-to-red photoconvertible fluorescent proteins (PCFPs) of the EosFP family are commonly used in ensemble pulse-chase and single-molecule localization or tracking approaches. However, these fluorescent proteins exhibit highly complex photophysical behaviors. In the green-form, recent NMR experiments revealed that mEos4b and other PCFP variants exist in two different conformational states at thermal equilibrium, which limits their effective photoconversion efficiency. Here, we investigate the conformational heterogeneity of mEos4b in the photoconverted red-form, employing a combination of solution NMR, UV–vis spectroscopy and fluorescence imaging. Only a single red population of mEos4b is observed at thermal equilibrium. However, a second population emerges under illumination with 405 or 488 nm light, which slowly decays in the dark or can be swiftly reverted under 561 nm light. This second population manifests itself through a pH-dependent positive photoswitching mechanism that adds to the already characterized negative photoswitching assigned to cis–trans isomerization of the chromophore. Our data indicate that positive photoswitching, instead, results from the light-induced formation of a second fluorescent state with a cis configuration of the chromophore that exhibits a substantially increased pK_a. Such a mechanism, suggested to result from rewiring of the H-bonding network around the first amino acid of the chromophore, adds to the panoply of switching scenarios observed in fluorescent proteins. It bears consequences for the spectroscopic characterization of PCFPs, reduces their apparent brightness and generates short-lived off-times perturbing single-molecule localization microscopy applications.

Direct electrochemical ethylene-to-ethylene glycol (C₂H₄-to-EG) conversion can potentially reduce the consumption of fossil fuels and the emission of carbon dioxide (CO₂) compared with the traditional thermo-catalytic approach. Palladium (Pd) prepared by electrodeposition is represented as a promising electrocatalyst; however, it exhibits low Ethylene glycol (EG) current density (<4 mA cm^–2), Faradaic efficiency (<60%), and productivity (<10 μmol h^–1), hindering practical applications. Herein, we report a nanodendrite palladium catalyst supported on a large-area gas diffusion electrode. This catalyst gives high EG current density (12 mA cm^–2) and productivity (227 μmol h^–1) but low Faradaic efficiency (65%). With further Cl^– ions modification, Faradaic efficiency increased to a record-high value of 92%, and EG current density (18 mA cm^–2) and productivity (∼340 μmol h^–1) were also promoted. Experimental data suggest that the strong electron-withdrawing feature of Cl^– reduces the oxidation ability of in situ generated Pd–OH species, inhibiting EG overoxidation to glycol aldehyde. Meanwhile, Cl^– alters EG adsorption configuration─from parallel and dual-site coordination to vertical and single-site coordination─over the Pd surface, thus preventing C–C bond cleavage of EG to CO₂. In addition, Cl^– adsorption facilitates the generation of Pd–OH active species to improve catalytic activity. This work demonstrates the great potential of surface ion modification for improving activity and selectivity in direct electrochemical C₂H₄-to-EG conversion, which may have implications for diverse value-added chemicals electrosynthesis.

Chiral spirocycles possess the ability to undergo diverse modifications in three-dimensional space, offering advantages in terms of physicochemical property and structural variability over conventional organic scaffolds and holding promising potential for the design of biologically active molecules and drugs. Among them, highly strained spirocyclobutanes with multiple chiral center-containing four-membered rings have attracted significant attention, but their viable and efficient synthesis poses a great challenge. By virtue of cage-confined asymmetric photocatalysis, we successfully construct spirocycle and bispirocycle compounds containing multiple quaternary and tertiary chiral carbon centers in cyclobutane rings through cross [2 + 2] photocycloaddition with visible-light-induced and mild reactions. The mechanistic studies unveil that the chiral open pockets of a cage photoreactor facilitate dynamic bimolecular recognition to render preferential heteromolecular cross-cycloaddition with enhanced reactivity, unconventional enantioselectivity, and good substrate tolerance, providing a promising direction for enzyme-mimetic catalyst design for challenging asymmetric photochemical transformations.

The many emerging applications of nanoparticles in diverse fields in chemistry and biology require the characterization of interactions between nanoparticles and surrounding biomolecules such as proteins. Nuclear magnetic resonance spin relaxation of proteins, which is highly sensitive to interactions with nanoparticles, contains rich information about protein mobility and binding kinetics. The interactions of globular proteins with silica nanoparticles differ markedly from those with liposome nanoparticles, although both are driven by electrostatic forces. For unmodified silica nanoparticles, their interactions with an internally rigid protein like ubiquitin uniformly increase the backbone amide ¹⁵N transverse R₂ relaxation for most residues. In contrast, for ubiquitin-POPG liposome interactions, their characteristic transverse R₂ profiles indicate that ubiquitin undergoes diffusive rotational motions on the liposome surface. Here, we show that coating silica nanoparticles with sulfobetaine siloxane zwitterionic molecules profoundly alters their interactions with proteins in a manner that closely resembles the mode of interaction observed with liposomes. ¹⁵N-R₂ relaxation reveals that ubiquitin and the Ras-binding domain of B-Raf both exhibit axial reorientational motions about an axis perpendicular to the nanoparticle surface in the bound state, where the interactions involve predominantly positively charged surface regions. These findings point toward a global dynamics mechanism of proteins when interacting with organic or inorganic nanoparticles with densely charged soft surfaces. This information may help tailor the coatings of nanoparticles to adopt specific modes of interaction with proteins that can be used to control their function in vivo and in vitro.

Surface-assisted laser desorption/ionization (SALDI) offers promising prospects for mass spectrometry detection and imaging of small biomolecules, as it addresses most of the matrix-related issues encountered in conventional matrix-assisted laser desorption/ionization (MALDI). Currently, nearly all of the fundamental aspects and applications of SALDI depend on nanosecond (ns) lasers, whereas few efforts have been made to integrate ultrafast femtosecond (fs) lasers with SALDI. Therefore, the intrinsic fundamental principle remains poorly understood. Herein, a novel surface-assisted femtosecond laser desorption/ionization mass spectrometry (fs-SALDI-MS) platform was developed, which significantly reduces analyte fragmentation and preserves molecular integrity. Spectral interferences from surface-assisted materials and alkali-metal adducts are absent in fs-SALDI mass spectra. Ion survival yields continuously increase with decreasing laser pulse widths from 5 ns to 600 fs, highlighting a gradual transition from thermal to nonthermal effects. A lower absolute limit of detection down to ∼3 amol for representative antifungal and psychotropic drugs and clearer visualization of ultratrace drug residues on latent fingerprints can be achieved, indicating that fs-SALDI results in gentler and more efficient detection/ionization processes than mainstream ns-SALDI. The biological applicability of this method was further validated through 10 μm-spatial-resolution lipid imaging of mouse brain sections. In short, a novel Coulomb field-driven desorption/ionization mechanism is proposed for fs-SALDI, opening new avenues for the development of emerging fs-SALDI techniques with superior analytical performance.

To realize human-machine fusion, a hybrid neural pathway operating in the same modality with biological systems becomes imperative, which requires an interneuron unit to encode information in biorecognizable spike sequences and tune the frequency upon excitatory and inhibitory neurotransmitters. Existing artificial interneurons cannot encode information upon different neurotransmitters, and the activation threshold and frequency responsivity do not align with those of biological counterparts, leading to limited success in constructing a signal-harmonizing hybrid neural pathway for neuroprosthetics, neurorehabilitation, and other neuroelectronic applications. Herein, we develop a bipolar-chemosynapse interneuron to encode the spike frequency in a highly bionic paradigm. Bipolar synapses dynamically respond to excitatory and inhibitory neurotransmitters and translate time-series chemical signals into the spike sequence, achieving the lowest activation threshold (6.25 μM) and the highest frequency responsivity (0.55 Hz μM^–1) to date, close to the biological counterpart. A signal-harmonizing hybrid sensorimotor pathway mediated by excitatory and inhibitory neurotransmitters is constructed for the first time, which encodes upstream mechanical stimuli, modulates the downstream leg swing frequency of a mouse, and balances neural activity accordingly.

Developing solvents with balanced physicochemical properties for high-voltage cathodes and lithium metal anodes is crucial for a sustainable and intelligent future. Herein, we report fully methylated tetramethyl-1,3-dimethoxydisiloxane (TMMS) as a single solvent for lithium metal batteries. We demonstrate that the fully methylated structure and Si–O bonds within TMMS can effectively elevate the dehydrogenation energy barrier, migrating the oxidation decomposition of the electrolyte. Additionally, the weak solvating power of TMMS favors the formation of an anion-rich solvation structure that induces the generation of an inorganic-rich electrode/electrolyte interphase layer at both the cathode and anode. Accordingly, the formulated electrolyte exhibits remarkable stability against high-voltage cathodes and lithium metal anodes. Notably, LiNi_0.8Co_0.1Mn_0.1O₂||Li (NCM811||Li) full cells with TMMS-based electrolytes realize a significant improvement in capacity retention compared with a dimethoxyethane-based electrolyte at both room temperature and 50 °C. This work provides insight into full methylation and the Si–O bond strategy and paves the way for the development of high-voltage lithium metal batteries.

We report that the cationic iridium complex (^iPrPCP)IrH⁺ catalyzes the transfer-dehydrogenation of alkanes to give alkenes and hydrogen isotope exchange (HIE) of alkanes and arenes. Contrary to established selectivity trends found for C–H activation by transition metal complexes, strained cycloalkanes, including cyclopentane, cycloheptane, and cyclooctane, undergo C–H addition much more readily than n-alkanes, which in turn are much more reactive than cyclohexane. Aromatic C–H bonds also undergo H/D exchange much less rapidly than those of the strained cycloalkanes, but much more favorably than cyclohexane. The order of reactivity toward dehydrogenation correlates qualitatively with the reaction thermodynamics, but the magnitude is much greater than can be explained by thermodynamics. Accordingly, the cycloalkenes corresponding to the strained cycloalkanes undergo hydrogenation much more readily than cyclohexene, despite the less favorable thermodynamics of such hydrogenations. Computational (DFT) studies allow rationalization of the origin of reactivity and the unusual selectivity. Specifically, the initial C–H addition is strongly assisted by β-agostic interactions, which are particularly favorable for the strained cycloalkanes. Subsequent to α-C–H addition, the H atom of the β-agostic C–H bond is transferred directly to the hydride ligand of (^iPrPCP)IrH⁺ to give a dihydrogen ligand. The overall processes, C–H addition and β-H-transfer to hydride, are calculated to generally have minima on the IRC surface although not necessarily on the enthalpy or free energy surfaces; these minima are extremely shallow such that the 1,2-dehydrogenations are effectively concerted although asynchronous.

An accelerated development of durable and affordable sustainable energy technologies is often hindered by a limited understanding of how nonprecious materials within these systems degrade. In acidic proton exchange membrane fuel cells and water electrolyzers, metallic cobalt (Co) is considered an unstable component that is often combined with precious metals or other stabilizers. To understand the mechanisms behind Co instability, we employ an experimental platform that quantifies dissolution with on-line inductively coupled plasma mass spectrometry and product formation with electrochemical mass spectrometry during electrochemical testing, along with ex situ characterization. Under varied conditions (electrocatalysis, time, gas-type saturation, and ion concentration), windows of Co stability are observed that are different than predicted with classical chemical thermodynamics, suggesting new stabilization and degradation mechanisms than previously understood. Notably, Co is active for the hydrogen evolution reaction (HER), with prolonged stability that is ∼300 mV greater than thermodynamically projected. Additionally, in an oxygenated environment, Co concurrently performs the HER and the oxygen reduction reaction (ORR) yet undergoes different morphology changes and dissolution mechanisms. Interestingly, at open-circuit voltage, there is a 22× decrease in dissolution in an oxygen-free environment, proposing a route to decrease Co losses during device shutdown protocols. Lastly, under more extreme operating conditions, Co becomes stable after a substantial amount of dissolution, suggesting that high concentrations of Co²⁺ ions in the microenvironment induce the formation of a stable CoHO₂ surface. Altogether, these results can be leveraged to improve the design and development of more robust and cost-effective sustainable energy technologies, as well as promote strategic strategies for prolonged material utilization.

Triterpenoids and steroids are structurally complex polycyclic natural products with potent biological functions, for example, as hormones. In all eukaryotes, the carbon skeletons of these compounds are generated by oxidosqualene cyclases, which carry out a polycyclization cascade to generate four or five rings with up to nine stereogenic centers in a targeted manner. The tight stereochemical control of this cascade reaction severely limits the stereochemical space accessible by known oxidosqualene cyclases. Considering that naturally occurring hormone stereoisomers have markedly different biological activities, finding ways to produce stereoisomers of triterpenes would be highly desirable to open new avenues for developing triterpenoid and steroid drugs. Here, we present a plant kingdom-wide sequence mining approach based on sequence similarity networks to search for noncanonical oxidosqualene cyclases that might produce triterpene stereoisomers. From 1,891 oxidosqualene cyclase sequences representing the diversity of green plants, six candidates were selected for functional evaluation by heterologous production in Nicotiana benthamiana. Of these six candidates, three produced rare or previously inaccessible triterpene stereoisomers, namely, (3S,13S)-malabarica-17,21-diene-3β,14-diol, 19-epi-lupeol, and a previously unknown hopanoid stereoisomer that we call protostahopenol. Site-directed mutagenesis revealed key residues important for catalytic activity. The sequence similarity network mining strategy employed here will facilitate the targeted discovery of enzymes with unusual activity in higher organisms, which are not amenable to common genome mining approaches. More importantly, our work expands the accessible stereochemical space of triterpenes and represents the first step to the development of new triterpenoid-derived drugs.

Chiral 1-tetrahydronaphthamides are the core structures of many bioactive molecules, yet their efficient asymmetric synthesis from a simple feedstock remains a challenge. Herein, we present a one-pot synthesis strategy that combines electrochemical reduction and ruthenium-catalyzed asymmetric hydrogenation to achieve the enantioselective reduction of 1-naphthalenamides to chiral 1-tetrahydronaphthamides. The protocol provides a practical platform for selectively constructing high-value chiral tetrahydronaphthenes from readily available naphthalene feedstock, thereby expanding the scope of asymmetric hydrogenation. The synthetic utility of this protocol is further demonstrated through the synthesis of bioactive molecules.

Glycoproteins are often considered as drug candidates. However, the regulation of post-translational glycan attachment remains an issue. We hypothesized that replacing the oxygen atom in the glycosidic linkage with sulfur atoms would stabilize the labile linkage against glycosidases, resulting in improved pharmacokinetics. In this study, we focused on the macrophage-activating factor (MAF) carrying O-linked N-acetylgalactosamine (GalNAc) and creating a miniature glycopeptide associated with MAF. A partial structure of MAF with a chemical mutation at three amino acid residues was designed in which threonine was replaced with cysteine (Cys), leading to a thioglycosidically linked GalNAc and a conformationally stable cyclic peptide due to the disulfide bond. GalNAc-Cys was used in solid-phase peptide synthesis, and the desired cyclic glycopeptide was synthesized. In the synthesis of GalNAc-Cys, glycosylation reactions were carried out based on the hard and soft acids and bases concept, where glycosyl trichloroacetimidate and fluoride were successfully used to couple with the thiol group in Cys. GalNAc-Cys was also evaluated as a substrate of α-GalNAc-ase and was shown to resist hydrolysis, supporting our concept. The synthesized cyclic miniature MAF induced LPS-assisted IL-12 production and resisted against α-GalNAc-ase.

Disclosed here is a catalytic enantioselective nucleophilic α-fluorination of simple ketones. A new hydrogen bonding donor catalyst was designed to not only overcome the competing catalyst deactivation but also enable efficient enantiocontrol in C–F bond formation between racemic α-keto sulfoniums and CsF. Careful condition optimization resulted in a general and mild protocol applicable for the configurational flexible acyclic α-fluoro ketones bearing a tertiary stereogenic center, thus complementary to the previous electrophilic fluorination methods that were only effective to cyclic ketones and/or tetrasubstituted stereogenic centers. Preliminary mechanistic studies support a phase transfer and dynamic kinetic resolution pathway operated by HBD-enabled anion-binding.

The 1-dihydrobenzazepine skeleton has emerged as a privileged structural motif in bioactive molecules. However, due to a lack of asymmetric methodology, access to chiral 1-dihydrobenzazepines has remained limited. Herein, we report the first intermolecular asymmetric cycloisomerization of benzo-fused enynes for the synthesis of chiral 1-dihydrobenzazepines via dirhodium catalysis. This methodology features high efficiency (up to 98% yield), high enantioselectivity (up to 99% ee), and broad scope of nucleophiles, including oxygen nucleophiles (alcohols, phenols, and carboxylic acids) and carbon nucleophiles (silyl enol ethers). Theoretical and experimental mechanistic studies reveal that the reaction pathway encompasses an asymmetric cycloisomerization, which gives rise to a dirhodium carbene containing a donor–acceptor (D-A) cyclopropane moiety, followed by a ring-opening process and stereoselective nucleophilic attack by external nucleophiles on the cyclopropyl ring. Control experiments demonstrate the pivotal role of the terminal group capped on the alkynyl group of substrates in achieving good efficiency.

The partial hydrogenation of waste polyethylene terephthalate (PET) offers a great opportunity to produce valuable chemicals, yet achieving precise catalytic control remains challenging. Herein, for the first time, we realized one-pot selective hydrogenation of waste PET to p-toluic acid (p-TA) with a record-high yield of 53.4%, alongside a 36.4% yield of p-xylene (PX), using a specially designed PtW/MCM-48 catalyst. Mechanistic investigations revealed that the exceptional catalytic performance arises from synergistic interaction between Pt nanoparticles and WO_x species. Low-valent WO_x enhances Pt dispersion, while Pt stabilizes WO_x as low-polymerized polytungstates. The moderate acidity of PtW_1.5/MCM-48 ensures controlled desorption of p-TA, preventing overhydrogenation to PX. The catalyst demonstrated robust performance with real-world PET waste. Life cycle assessment and technical and economic evaluation further highlight its practical feasibility. This study establishes a sustainable pathway for PET chemical upcycling and provides a framework for designing advanced catalysts for selective hydrogenation reactions, addressing critical challenges in circular chemistry and plastic waste management.

Tumor-derived extracellular vesicles (tEVs) are essential mediators of tumor progression and therapeutic resistance, yet their secretion dynamics and cargo composition in response to therapies remain poorly understood. Here, we present STAMP, specific click-tagging driven by aptamer for tEV labeled with a metabolic timestamp, which exploits the unique kinetics and thermodynamics of aptamer to significantly enhance the local concentration of clickable probes on tEVs for their covalent attachment to the timestamp, resulting in the selective microfluidic isolation of nascent tEVs following stimulation. In a PD-L1 antibody-treated model, we demonstrated the feasibility of STAMP and revealed a robust positive correlation between the nascent EpCAM⁺ EV levels and tumor volume. Proteome profiling of isolated nascent tEVs identified previously unknown upregulated vesicle proteins following immunotherapy, including key regulators of immune activation and suppression, suggesting that tumors orchestrate an intricate dual adaptive response through tEV secretion modulation to simultaneously elicit therapeutic sensitivity and resistance. Notably, among the upregulated proteins, we identified HSP70, whose enhanced presentation on tEVs promotes antitumor immunity and inhibits tumor growth. Thus, STAMP provides an effective gateway for studying EV dynamics with cell-origin accuracy and for identifying potential therapeutic targets based on EV transitions.

Aeruginosins are linear peptide natural products isolated from cyanobacteria and contain various arginine derivatives at their termini. 1-Amino-2-(N-amidino-3-Δ3-pyrrolinyl)ethane (Aeap) is a structurally unique arginine derivative, as it has an unusual pyrroline ring with two additional carbon atoms of unknown biosynthetic origin. Here, we demonstrate that Aer3, a member of a newly identified subfamily of prenyltransferases, catalyzes selective isopentenylation of the internal N atom of agmatine. Rieske oxygenase AerC then catalyzes both carbocyclization and C–C bond cleavage to construct the pyrroline ring in Aeap. This pyrroline ring formation in Aeap biosynthesis, involving two novel enzymes, represents a unique route for heterocycle formation in nature.

The ammonia electrooxidation reaction (AOR) has attracted significant attention for both wastewater treatment and energy storage applications. However, AOR pathways generating oxygenated products such as nitrite or nitrate remain unresolved. Attenuated total reflection–surface-enhanced infrared absorption spectroscopy (ATR–SEIRAS) and density functional theory (DFT) have been combined to determine the potential-dependent intermediates, active catalytic sites, and AOR pathways on Ni electrodes under alkaline conditions. The OH/O vacancy sites on NiOOH, revealed by XPS, are found by DFT calculations to be the active sites for the AOR, catalyzing the complete (eight-electron) oxidation of ammonia into nitrate. The formation of isolated OH/O vacancies on NiOOH is thermodynamically more favorable than that of paired vacancies in the potential range conducive to NiOOH formation and the AOR, with an increasing formation barrier at higher potentials. This synergistic ATR–SEIRAS and DFT study reveals that the selectivity of nitrite and nitrate production is potential-dependent, with nitrite and hydrazine formation initiated at moderate anodic potentials, whereas larger potentials promote conversion of nitrite into nitrate species. The release of adsorbed nitrite and nitrate, which is crucial for liberating catalytic sites for the continuous AOR, is spectroscopically and computationally shown to be facilitated at relatively low potentials. Comprehending AOR mechanisms on Ni-based catalysts as achieved in this study can pave the way for future research on catalyst design and optimization of AOR performance.

C–N axially chiral compounds represent an important class of atropisomers that are prevalent in bioactive and material molecules. Despite recent advances in synthetic methodologies, the asymmetric construction of atropisomers featuring multiple C–N axes has been rarely explored, significantly limiting their further applications. Herein, we report a novel atroposelective synthesis of diaxially chiral pyridoindolones featuring both six–five and six–six C–N axes through cobalt-catalyzed asymmetric C–H annulation. This approach demonstrates exceptional efficiency, yielding a diverse array of chiral pyridoindolones with excellent yields and atroposelectivities (60 examples, up to >99% yield, >99% ee, and >20:1 dr). Mechanistic studies revealed that the stereochemistry of both C–N axes were generated and fixed simultaneously during the C–H cyclometalation step, along with an unexpected asymmetric amplification effect. The practicality of this protocol is further underscored by successful gram-scale syntheses and various transformations, including the formation of a chiral phosphine ligand. Notably, exceptional photoluminescence quantum yields (Φ_F up to 0.99) and positive solvatochromism were observed, coupled with significant chiroptical properties, underscoring the potential applications of these compounds in organic fluorescent materials.

The performance of the electrocatalytic CO₂ reduction reaction (CO₂RR) is highly dependent on the microenvironment around the cathode. Despite efforts to optimize the microenvironment by modifying nanostructured catalysts or microporous gas diffusion electrodes, their inherent disorder presents a significant challenge to understanding how interfacial structure arrangement within the electrode governs the microenvironment for CO₂RR. This knowledge gap limits fundamental understanding of CO₂RR while also hindering efforts to enhance CO₂RR selectivity and activity. In this work, we investigate this knowledge gap using a tunable system featuring superhydrophobic hierarchical Cu nanowire arrays with microgrooves (NAMs). Adjusting the NAM structure tunes multiple synergistic effects in the microenvironment, which include stabilization of the microwetting state, confinement of CO*, improvement to local CO₂ concentration, and modulation of the local pH. Notably, using mass transport modeling, we quantify the role of the gas–liquid–solid interface in boosting local CO₂ concentrations within several microns of the interface itself. Leveraging these effects, we elucidate how CO* and H* competitively occupy active sites, influencing reaction pathways toward multicarbon products based on tuning the microenvironment. Consequently, we provide new insights into why the optimized configuration significantly increased CO₂RR activity by 690% (as normalized by electrochemical active surface area), C₂₊ product selectivity by 72%, and Faradaic efficiency by 36%, compared to CO₂RR with hydrophobic Cu foil. Based on these insights, our findings unlock new opportunities to engineer the CO₂RR microenvironment through the rational organization of hierarchical interface materials in gas diffusion electrodes toward improved CO₂RR selectivity and activity.

Lithium argyrodites Li₆PS₅X (X = Cl, Br, I) are a promising class of solid-state electrolytes with the potential to achieve high conductivities (>10 mS·cm^–1) necessary for use in solid-state batteries. Previous research has shown that structural factors, in particular, site disorder between the sulfide and halide anions, can impact the ionic conductivity of lithium argyrodites. One current hypothesis for this correlation between anion site disorder and ionic transport is a connection to the lithium-ion substructure. However, as there is limited research surrounding the anion disordering process itself, this relationship has yet to be fully understood. This research explores the impact of the composition and synthesis on the anion disordering process through the Li_6+xP_1–xSi_xS₅Br (x = 0 to 0.4 in 0.1 steps) series of substitutions quenched from different annealing temperatures. Ex situ and in situ diffraction studies show that the anion site disorder within the compounds increases upon Si introduction only for samples quenched from higher annealing temperatures but remains relatively constant at lower annealing temperatures. Based on in situ diffraction measurements, we further monitor the effects of anion mobility at elevated temperatures allowing inference of slower anion disordering kinetics with changing compositional content. We complement the experimental work using nudged-elastic band calculations showing the overall preference of anions for their specific sites and the possibility of anion mobility. This work provides insight into the argyrodites and shows that the anion disordering can be monitored and that the composition has strong influences on the disordering process.

In this study, the role of phosphorylation in the liquid–liquid phase separation (LLPS) of tau, the underlying driving forces, and the potential implications of this separation on protein conformation and subsequent protein aggregation were investigated. We compared in vivo-produced phosphorylated tau (p-tau) and nonphosphorylated tau under different coacervation conditions without adding crowding agents. Our findings revealed that spontaneous phase separation occurs exclusively in p-tau, triggered by a temperature shift from 4 °C to room temperature, and is driven by electrostatic and hydrophobic interactions. The p-tau self-acervation is reversible with temperature changes. Native mass spectrometry detects only two to nine phosphate groups per p-tau molecule, highlighting the impact of phosphorylation on tau’s structural flexibility. Cross-linking mass spectrometry showed fewer long-range contacts in p-tau, suggesting a looser conformation induced by phosphorylation. Phosphorylation-induced LLPS and RNA-induced LLPS occurred at different timeframes. However, neither tau nor p-tau formed fibrils without the addition of dextran sulfate or RNA as inducers. Using human kidney epithelial cells expressing the tau R domain fused with fluorescent proteins as reporter cells, we observed aggregates in the nuclear envelope (NE) only in the cells treated with LLPS-state p-tau, which correlates with NE occurrences reported in Alzheimer’s disease brain sections. These findings provide deeper insights into the impact of phosphorylation on tau aggregation through an intermediate condensation phase, offering novel perspectives on neurodegenerative disease mechanisms.

We report the cosolvency effect of formamidinium lead triiodide (FAPbI₃) in a mixture of γ-butyrolactone (GBL) and 2-methoxyethanol (2ME), a phenomenon where FAPbI₃ shows higher solubility in the solvent blend than in either alone. We found that FAPbI₃ exhibits 10× higher solubility in 30% 2ME in GBL than in 2ME alone and 40% higher solubility than in GBL alone at 90 °C. This enhanced solubility is attributed to the disruption of the hydrogen bonding network within 2ME, allowing its hydroxyl and ether groups to interact more freely with the solute. Leveraging this phenomenon, we grew phase-stable α-FAPbI₃ thin single crystals under ambient air conditions with no doping. Compared to conventional cesium-doped FAPbI₃, the undoped FAPbI₃ single-crystal films exhibited lower defect densities and enhanced charge retention and transfer while also avoiding phase segregation linked to cesium incorporation. Solar cells fabricated with these ambient-air-grown single-crystal films achieved an efficiency of 21.56% (17.72% for cesium-doped FAPbI₃), retaining 90% of performance after six months of storage. These findings advance our understanding of perovskite solubility in solvent blends and offer an efficient pathway for producing stable, high-efficiency FAPbI₃ single-crystal solar cells through ambient air fabrication, overcoming the limitations of doping.

Semiconductor devices often rely on high-purity materials and interfaces achieved through vapor- and vacuum-based fabrication methods, which can enable precise compositional control down to single atomic layers. Compared to groups IV and III–V semiconductors, hybrid perovskites (HPs) are an emergent class of semiconductor materials with remarkable solution processability and compositional variability that have facilitated rapid experimentation to achieve new properties and progress toward efficient devices, particularly for solar cells. Surprisingly, vapor deposition techniques for HPs are substantially less developed, despite the complementary benefits that have secured vapor methods as workhorse tools for semiconductor fabrication. For instance, metal organic chemical vapor deposition (MOCVD) emerged in the late 1960s as a vital tool to enable production of compound semiconductor and heterojunction devices, giving rise to tremendously important technologies such as solid-state lighting and diode lasers, yet there is no analogous MOCVD process for HPs. Here, using a custom-built two-zone reactor, we report the first MOCVD process for the direct vapor deposition of thick and continuous films of methylammonium lead halide (MAPbX₃; X = Br, I) from distinct organolead, halide, and amine vapor sources. Mechanistic investigation via kinetic studies and density functional theory (DFT) calculations suggest a multistep reaction mechanism that should be generalizable to a broad set of HP materials. We anticipate that the continued development of generic HP MOCVD processes will unlock compositional, crystallographic, and morphological control complementary to solution methods, enabling the rational design of material properties and pursuit of new applications.

Raman-based theranostics has demonstrated great potential for sensitive real-time imaging and treatment. However, these advanced materials, primarily depending on the SERS technique, encounter clinical concerns regarding substrate biosafety. Herein, we molecularly engineered a de novo substrate-free SICTERS small molecule, namely BTT–TPA (bis-thienyl-substituted benzotriazole selenadiazole derivative structures), possessing both ultrasensitive Raman signals and excellent photothermal effects based on self-stacking. The mechanistic studies confirm that BTT maintains the planar structure with polycyclic distorted vibrations required for SICTERS. TPA enhances the donor–acceptor interaction, yielding a Raman sensitivity of BTT higher than previously reported SICTERS molecules; it also acts as a molecular rotor, increasing the photothermal conversion efficiency to 67.44%, which is superior to most of the existing SERS-based photothermal materials. In the tumor model of mouse orthotopic colon cancer, BTT–TPA NPs demonstrate a great Raman imaging-guided photothermal therapy effect in eliminating primary and metastatic tumors, remarkably decreasing the recurrence rate. This work puts forward substrate-free SICTERS small molecules toward Raman-based theranostic applications in vivo.

Reducing the formation overpotential of key reaction intermediates represents a major challenge in developing broad electrocatalytic reactions. Recent vibrational spectroscopic studies of electrochemical CO₂ or CO reduction reaction (CO₍₂₎RR) characterized an interesting formation of stochastic CO (CO_stochastic) intermediate with negligible energy losses under certain circumstances. Yet, the precise formation conditions and mechanisms remain unclear, hindering the correct understanding of related spectroscopic results and utilization of these effects to develop the CO₍₂₎RR and other electrocatalytic reactions. Herein, we combine in situ attenuated total reflection infrared absorption (ATR-IR) and Raman spectroscopies to systematically study the origins and generation mechanisms of these CO_stochastic. We reveal for the first time that the CO_stochastic originates from plasmonic excitation of Cu by laser excitation and exists only in in situ Raman but not in ATR-IR measurements utilizing the exact same catalysts and electrochemical cell. Both the illumination wavelength and the fluence are important for the formation of CO_stochastic. Furthermore, the surface speciation of the catalyst, i.e., the copresence of mixed metallic Cu⁰ and Cu⁺ states, is discovered to be crucial for the formation of CO_stochastic. These results demonstrate that mechanistic studies of the CO₍₂₎RR and other electrocatalytic reactions utilizing in situ Raman spectroscopy must carefully control the excitation fluence to avoid signals due to plasmonic excitations of the catalysts other than the electrochemical processes. Meanwhile, plasmon-enhanced electrochemistry, although still impractical for promoting CO₂RR under ordinary illumination, may inspire new strategies for designing light-driven electrochemical reactions at extremely low overpotentials.

Developing active, stable, and cost-effective acidic oxygen evolution reaction (OER) catalyst is a critical challenge in realizing large-scale hydrogen (H₂) production via electrochemical water splitting. Utilizing highly active and relatively inexpensive Ru is generally challenged by its long-term durability issue. Here, we explore the potential of stabilizing active Ru sites in Ru_x(Ir,Fe,Co,Ni)_1–x multicomponent alloy by investigating its phase formation behavior, OER performance, and OER-induced surface reconstruction. The alloy exhibited a multiphase structure composed of major face-centered cubic (fcc) and minor hexagonal close-packed (hcp) phases at near equimolar concentration. Machine-learned interatomic potential (MLIP) coupled with replica-exchange molecular dynamics was utilized to describe the atomic scale mixing behavior of the Ru_x(Ir,Fe,Co,Ni)_1–x catalysts and other RuIr-based alloys. The model supports our experimental findings of the well-mixed bulk fcc phase and provides an indication of the minor hcp phase formation. The optimized Ru_0.20(Ir,Fe,Co,Ni)_0.80 catalyst exhibited improved OER activity with an average overpotential of ∼237 mV measured at 10 mA cm^–2 and enhanced stability with a low activity degradation rate of ∼1.1 mV h^–1 in 24 h of operation. The acidic OER conditions induced the formation of a thin RuIr-rich oxide shell layer with a trace amount of 3d metals, where Ru was found to be relatively stabilized near the surface of the evolved nanoparticles. The machine learning-accelerated high throughput simulation protocol was further employed to screen other potential RuIr-containing quinary alloys based on expected phase stability. This work highlights the opportunity of stabilizing Ru in a multicomponent alloy matrix with improved activity and stability.

Electrochemical methodologies offer a transformative approach to sustainable chemical synthesis by enabling precise, energy-efficient transformations. Here, we report the selective electrochemical N-formylation of methylamine using methanol as both reagent and solvent, facilitated by a simple glassy carbon electrode. Under optimized conditions, we achieve a faradaic efficiency (FE) of 34% for methylformamide synthesis in a neutral NaClO₄ electrolyte. Mechanistic insights from in situ Fourier-transform infrared spectroscopy (FTIR) and complementary synthetic experiments reveal two distinct reaction pathways: the direct oxidation of a hemiaminal intermediate and a novel route involving the formation of methylisocyanide, which subsequently hydrates to yield methylformamide. The presence of methylisocyanide was confirmed through mass spectrometry analysis following a successful Ugi multicomponent reaction, demonstrating the ability to safely utilize reactive intermediates within an electrochemical framework. This work underscores the potential of electrosynthesis to unlock metal-free, sustainable pathways to produce value-added nitrogen-containing compounds, paving the way for greener approaches in chemical manufacturing and catalysis.

Carbenes are critical intermediates in organic chemistry, recognized for their exceptional reactivity and versatility. However, conventional methods for carbene generation are often associated with safety risks and hazardous procedures. This study presents a Ga-ZnO_1–x nanosheets photocatalyst with a (100) preferred orientation, featuring abundant refined frustrated Lewis pair (FLP) sites, excellent light absorption, and efficient charge transport properties. Under visible light irradiation, this catalyst activates methanol to generate a methyl carbene (methylene) intermediate, which subsequently reacts with another methanol molecule to produce ethanol. In situ experiments and theoretical calculations reveal that FLP sites, composed of oxygen vacancies and Ga, respectively activate C–H and C–O bonds while efficiently capturing photogenerated electrons and holes, making the most significant contribution to the formation of carbene intermediates. This research not only offers an eco-friendly route for methanol-to-ethanol conversion but also establishes a safer and more efficient method for methyl carbene production under mild conditions.

Sesquiterpene synthases (STSs) catalyze carbocation cascade reactions with various hydrogen shifts and cyclization patterns that generate structurally diverse sesquiterpene skeletons. However, the molecular basis for hydrogen shifts and cyclizations, which determine STS product distributions, remains enigmatic. In this study, an elusive STS SydA was identified in the biosynthesis of sydonol, which synthesized a new bisabolene-type sesquiterpene 6 with a unique saturated terminal pendant isopentane. Extensive evidence from isotope labeling experiments, crystal structures of SydA and its variant, quantum chemical calculations, and mutagenesis experiments reveal a plausible mechanism for the formation of 6 involving an unusual 1,7-hydride shift, which may be a key branchpoint for monocyclic, bicyclic, and tricyclic products. Structure-based engineering resulted in SydA variants that promote different reaction pathways, leading to the production of bicyclic α-cuprenene and (+)-β-chamigrene and tricyclic 7-epi-β-cedrene and β-microbiotene. These findings not only reveal a new bisabolene and its biosynthesis but also provide insights into the molecular basis of the hydride shifts and cyclizations, which pave the way for engineering STSs to produce complex terpenoid products.

The electric control of magnetism has been considered to be promising for molecular spintronics and quantum information. However, the spin-electric coupling strength appears to be insufficient for application in most cases. Two major factors capable of amplifying the relative effect are spin–orbit coupling and ferroelectricity. Herein, we chose four compounds as examples to study the contribution of spin–orbit coupling and ferroelectricity to spin-electric coupling. The relative orientation-dependent Hamiltonian terms were determined via electric-field modulated continuous-wave electron paramagnetic resonance. The origins of the spin-electric coupling effect in the four compounds are discussed and determined according to the characteristics of the experimental spectra. Meanwhile, the results demonstrated that strong spin–orbit coupling is crucial for producing significant spin-electric coupling and that the effect can be amplified by about 2 orders of magnitude by ferroelectricity. This work can guide the rational screen and design of materials with applicable spin-electric coupling strength, which may provoke techniques including low-power spintronics and precise manipulation of the quantum behavior of spins.

Metal halide perovskites have excellent optoelectronic properties. This study aims to determine how the optoelectronic properties of a model perovskite, cesium lead bromide (CsPbBr₃), change with length and thickness in one dimension (1D). By examining the photophysics of CsPbBr₃ quantum dots (QDs), nanowires (NWs), and nanorods (NRs), we observe the influence of confinement, exciton diffusion, and trapping on their optical properties. Our findings reveal that exciton diffusion to trap states limits the photoluminescence quantum yield (PLQY) of 1D CsPbBr₃ in the weakly confined regime (8–14 nm) and explains their long-lived exciton dynamics, while enhanced radiative rates contribute to achieving near-unity PLQY in the strongly confined regime (<7 nm). Consequently, blue-emitting, 2.4 nm-thick CsPbBr₃ NRs were 3.6X more emissive than the conventional CsPbBr₃ QDs. This study underscores how structural optimization can improve the optoelectronic performance of CsPbBr₃ and provides insight into the complex interplay of radiative and nonradiative processes in 1D ionic semiconductors.

The efficient removal of CO₂ from exhaust streams and even directly from air is necessary to forestall climate change, lending urgency to the search for new materials that can rapidly capture CO₂ at high capacity. The recent discovery that diamine-appended metal–organic frameworks can exhibit cooperative CO₂ uptake via the formation of ammonium carbamate chains begs the question of whether simple organic polyamine molecules could be designed to achieve a similar switch-like behavior with even higher separation capacities. Here, we present a solid molecular triamine, 1,3,5-tris(aminomethyl)benzene (TriH), that rapidly captures large quantities of CO₂ upon exposure to humid air to form the porous, crystalline, ammonium carbamate network solid TriH(CO₂)_1.5·xH₂O (TriHCO₂). The phase transition behavior of TriH converting to TriHCO₂ was studied through powder and single-crystal X-ray diffraction analysis, and additional spectroscopic techniques further verified the formation of ammonium carbamate species upon exposing TriH to humid air. Detailed breakthrough analyses conducted under varying temperatures, relative humidities, and flow rates reveal record CO₂ absorption capacities as high as 8.9 mmol/g. Computational analyses reveal an activation barrier associated with TriH absorbing CO₂ under dry conditions that is lowered under humid conditions through hydrogen bonding with a water molecule in the transition state associated with N–C bond formation. These results highlight the prospect of tunable molecular polyamines as a new class of candidate absorbents for high-capacity CO₂ capture.

Research on room temperature phosphorescence (RTP) of metal–organic frameworks (MOFs) has been rapidly developed in recent years. However, it is still challenging to realize long-wavelength RTP (>580 nm). In this article, a new strategy is proposed to achieve the red-shifted RTP through constructing dual-ligand MOFs. Different from the single-ligand MOF, which lacks intermolecular interaction, the dual-ligand MOF can build up a stable donor–acceptor (D-A) relationship between two suitable simple ligands. Therefore, the induced charge transfer (CT) process from the donor units to the acceptor units in the framework can decrease the energy gap between the frontier orbitals, reducing the excited state energy levels. Moreover, by modulating the electron density and conjugation of the acceptor ligand, the energy of the triplet states of MOFs can be further reduced. As a result, the RTP centered at 588 nm is successfully achieved in a dual-ligand MOF. Also, we clearly describe the electron transporting path among the ground, ¹CT, and ³CT states, revealing the emitting mechanism of the long-wavelength RTP. This work not only extends the D–A structure from the molecular level to the periodic structure of MOFs but also solves the problem of achieving long-wavelength RTP in MOFs from a new perspective.

The scientific community has been actively researching artificial photosynthesis to promote ecologically sustainable living and address environmental issues. However, designing photocatalysts with active sites that are effective for both CO₂ reduction and water oxidation remains a significant challenge. Thus, we present the development of a donor–acceptor covalent organic framework (D–A COF), that integrates two distinct metal coordination environments through structure–activity relationships. Either cobalt or nickel ion is anchored on the D–A COF backbone to create N-metal–nitrogen and N-metal–sulfur coordination configurations, serving as bifunctional reduction and oxidation active sites, respectively. Remarkably, the as-synthesized Co-Btt-Bpy COF generated CO at a rate of 9,800 μmol g^–1 h^–1 and O₂ at 242 μmol g^–1 h^–1 under visible light irradiation. The CO generation rate was 127 times higher than that of pristine D–A COF. More importantly, Co-Btt-Bpy COF facilitates artificial photosynthesis with a CO release rate of 7.4 μmol g^–1 h^–1. The outstanding photocatalytic performance can be attributed to the synergistic interaction between the dispersed single-atom sites and Btt-Bpy COF, as well as the rapid migration of photogenerated electrons. In situ attenuated total reflection Fourier transform infrared (ATR FT-IR) spectra and theoretical calculations indicated that introducing Co sites effectively lowered the reaction energy barriers for the crucial intermediates *COOH and *OH. This work provides state-of-the-art designs of photocatalysts at the molecular level and in-depth insights for efficient artificial photosynthesis.

The enzymatic synthesis of heterocycles is an emerging biotechnology for the sustainable construction of societally important molecules. Herein, we describe an enzyme-mediated strategy for the oxidative dimerization of thioamides enabled by enzymatic halide recycling by vanadium-dependent haloperoxidase enzymes. This approach allows for intermolecular biocatalytic bond formation using a catalytic quantity of halide salt and hydrogen peroxide as the terminal oxidant. The established method is applied to a diverse range of thioamides to generate the corresponding 1,2,4-thiadiazoles in moderate to high yields with excellent chemoselectivity. Mechanistic experiments suggest that the reaction proceeds through two distinct enzyme-mediated sulfur halogenation events that are critical for heterocycle formation. Molecular docking experiments provide insight into reactivity differences between biocatalysts used in this study. Finally, the developed biocatalytic oxidative dimerization is applied to a preparative scale chemoenzymatic synthesis of the anticancer agent penicilliumthiamine B. These studies demonstrate that enzymatic halide recycling is a promising platform for intermolecular bond formation.

Ferroelectrics with switchable spontaneous polarization have gained enormous attention for a century. However, the structural phase transitions of conventional ferroelectrics have been mainly limited to the ones with crystallographic point group changes accompanied by the breaking of spatial symmetry elements. Moreover, although chiral and photoswitchable ferroelectrics have both been of great interest in recent years, heteroatomic chiral photoswitchable ferroelectrics have never been reported. Herein, for the first time, we designed a pair of sulfur-chiral photoswitchable ferroelectrics (R_s and S_s)-N-(3-bromo-5-chloro-2-hydroxybenzylidene)-2-methylpropane-2-sulfinamide (1-R_s and 1-S_s). Notably, they undergo a structural phase transition from the chiral polar C2 to P2₁ space group of point group 2 at around 142 K, accompanied by the symmetry operation breaking from 2-fold rotation and screw rotation in C2 to only 2-fold screw rotation in P2₁. Such a structural phase transition with the same point group, while different space groups with the breaking of symmetry operations, is significantly distinct from the structural phase transition with different point groups and space groups in conventional ferroelectrics. Furthermore,1-R_s exhibits the highest piezoelectric d₃₃ value of 10 pC/N among organic photoswitchable ferroelectrics and shows optical control of ferroelectric polarization. To our knowledge, this is the first report of sulfur-chiral photoswitchable ferroelectrics showing phase transitions with only the space group change. This work enriches the family of chiral ferroelectrics and provides great inspiration for the exploitation of heteroatomic chiral photoswitchable ferroelectrics.

The ongoing discovery of highly reactive ambiphilic main-group species has significantly advanced the development of main-group chemistry, particularly in the realms of small molecule activation and catalysis. Theoretically, compounds featuring smaller HOMO–LUMO gaps gain stronger ambiphilicity and higher reactivity. In this work, we fundamentally demonstrate that Me₃Sb holds the smallest HOMO–LUMO gap among trimethylpnictines, indicating its outstanding ambiphilicity. Correspondingly, the superior reactivity of Me₃Sb toward deoxygenation of electron-deficient nitroarenes has been unambiguously revealed through control experiments. Furthermore, unprecedented Sb^III/Sb^VO cycling between trialkylstibines and their oxides has been established for the catalytic transformation of nitroarenes into azoxyarenes/azoarenes. This study opens a new chapter for organoantimony derivatives in the fields of ambiphilic reactivity and redox catalysis.

The presence of defects can significantly improve catalytic activity and stability, as they influence the binding of the reactants, intermediates, and products to the catalyst. Controlling defects in the structures of nanocrystal catalysts is synthetically challenging. In this study, we demonstrate the ability to control the growth of Ir nanocrystals, enabling the tuning of both structural and surface defects. The Ir nanocrystals have unique structures that range from single crystals of a few nanometers to twinned nanoparticles and multiply twinned crystallites with a high density of atomic steps. This approach of defect engineering enables us to understand their roles in enhancing the performance of the OER and producing an Ir catalyst with both high activity and stability. Our results show the importance of the concept of using synthetic control of structural and surface defects in metal nanoparticles as a strategy to improve catalytic performance.

Surface-catalyzed polymerization is crucial in both chemical science and industrial manufacturing, yet achieving regioselective radical polymerization on the surface remains challenging. Here, we demonstrate the regioselective Ullmann polymerization of nonsymmetrical 2,8-dibromoquinoline (DBQ) on an Au(111) surface. By combining scanning tunneling microscopy, density functional theory calculations, and kinetic modeling, we reveal the regioselectivity and its evolution with surface temperature at the molecular level. At 348–368 K, DBQ monomers primarily form covalent dimers through energetically favored head-to-head (HtH) coupling. As the temperature increases to 390–473 K, oligomers and long polymer chains are formed, with less favored head-to-tail (HtT) linkages emerging and eventually dominating over HtH linkages. Such regioselectivity evolution from HtH to HtT is suggested to be related to a sequential monomer addition mode and a shift in the distribution of reactive sites at the end and tail of the polymer chains during polymerization. This result provides molecular-level mechanistic insights into the regiochemistry of surface-catalyzed polymerization.

Asymmetric organocatalysis by bifunctional acid- and base-type small organic molecules has emerged as a promising way to enhance stereoselective organic transformations since the beginning of this millennium. Takemoto’s tert-amine/thiourea catalyst, an archetype in these endeavors, has encouraged many to design new multifunctional alternatives. However, the discovery of efficient catalysts in a library of thousands of candidates containing the desired functionalities in their structures remains a great challenge both synthetically and computationally. We, toward these ends, developed a computational protocol (CIPOC─Computational Identification of POtential (Organo)Catalysts), which discovered a chiral 2-aminoDMAP/urea catalyst among 1600 multifunctional catalyst candidates enabling conjugate addition of malonates to trans-β-nitroalkenes rapidly (in a few hours) with exquisite selectivities and yields, producing superior results than that of Takemoto’s. The unique activity of this chiral 2-aminoDMAP/urea is attributed to the dual function of the 2-aminoDMAP unit (double H-bonding and π-stacking interactions) in addition to the exceptional performance of the urea unit compared to thiourea, as a result of a lower energetic penalty required to distort the catalyst to its active conformation to provide optimal catalytic interactions.

We present a straightforward synthetic route to the novel chromium carbonyl-stabilized paramagnetic Sb₄-based cluster [Et₄N]₄[Sb₄Cr₆(CO)₂₈] ([Et₄N]₄[1]), which represented a rare example of the intact Sb₄ tetrahedron structurally characterized in the solid state. Complex 1 exhibited versatile reactivities toward groups 7–9 metal carbonyls, dioxygen, or [Cu(MeCN)₄][BF₄] to form selective orbital-controlled Sb₄-based products, including transmetalated paramagnetic complexes [Et₄N]₄[Sb₄Cr₅Mn(CO)₂₈]Br ([Et₄N]₄[1-Mn]Br), [Et₄N]₄[Sb₄Cr₂Fe₆(CO)₃₀] ([Et₄N]₄[1-Fe]), and [Et₄N]₂[Sb₄Cr₄Co₄(CO)₃₁] ([Et₄N]₂[1-Co]), the dioxygen-activated paramagnetic cluster [Et₄N]₄[O₂Sb₄Cr₆(CO)₂₈] ([Et₄N]₄[1-O₂]), or the spin-quenched complex [Et₄N]₂[Sb₄Cr₆(CO)₂₈] ([Et₄N]₂[2]), respectively. The structural nature, bonding properties, paramagnetism, and semiconductivity of these unprecedented transition metal carbonyl-protected Sb₄-based clusters were further realized with DFT calculations.

Electrochemical nitroarene reduction enables the green production of anilines at ambient conditions thanks to the manipulated transfer of multiple electrons and protons via controlling potentials and currents, but challenges remain in pH-neutral electrolysis using nonprecious catalysts. Here, Chevrel phase Mo₆S₈ with high conductivity and insertable frameworks is proposed for the first time as a cost-efficient candidate with prominent performance and, more importantly, as a new platform to unravel cation effects on nitroarene electroreduction. Nanosized Mo₆S₈ derived from polymer-confined sulfidation affords a high yield (∼95%) and Faradaic efficiency (∼99%) for reducing 4-nitrostyrene to 4-aminostyrene at −0.45 V (vs RHE) in 0.1 M LiClO₄, outperforming a series of counterparts of metal sulfides and even noble metals. The combination of experimental and theoretical analyses identifies an intercalation-correlated cation effect, expanding the current knowledge limited to the outer Helmholtz plane of electrodes. In situ Li⁺ intercalation into Mo₆S₈ cavities during electrolysis ameliorates the electronic configurations and thereby promotes the adsorption of the nitro group on low-coordinated Mo sites for hydrogenation via a proton-coupled electron transfer mechanism. Furthermore, the efficient electrosynthesis of aniline derivatives with conserved reducing groups from a wide range of substrates highlights the promise of Mo₆S₈ for electrochemical refinery.

Trichothecenes are a widespread family of sesquiterpenoid toxins that can pose significant risks to food and feed safety as well as environmental health. A defining feature of all trichothecenes is their central tricyclic 12,13-epoxytrichothec-9-ene (EPT) motif. Although the formation of the EPT central skeleton has long been presumed to be a spontaneous process, the nonenzymatic cyclization reaction forming the tetrahydropyran ring in EPT requires acid catalysis; otherwise, it occurs too slowly to sustain efficient trichothecene biosynthesis under physiological conditions. Here, we resolved this decades-old problem by identifying the missing enzymes for EPT biosynthesis. We demonstrate that the C11 hydroxyl group of universal trichothecene precursors, isotrichodiol and isotrichotriol, must be acetylated by a strictly conserved O-acetyltransferase Tri3 to furnish a better leaving group. These acetylated intermediates preferentially undergo spontaneous allylic rearrangement with water to give shunt products, trichodiol and trichotriol. Therefore, a novel cyclase, Tri14, which was previously annotated as a hypothetical protein, is required to overcome the kinetically unfavored oxide bridge closure and meanwhile suppress the spontaneous formation of any shunt products.

The electrocatalytic oxidation of benzyl alcohol to benzoic acid is a process that often requires high voltage, leading to increased energy consumption, side reactions (oxygen evolution reaction (OER)), and catalyst degradation. Herein, our study introduces a novel approach. We demonstrate that a PtZn-ZnO_x catalyst featuring a PtZn intermetallic structure with abundant PtZn-ZnO_x interfaces on the surface allows for the electrocatalytic oxidation of benzyl alcohol to benzoic acid with an impressive selectivity of 99.5% at a low potential of 0.725 V (vs a reversible hydrogen electrode, RHE), which is 0.6 V lower than most reported studies. This high selectivity is a testament to the efficiency of our catalyst, as it significantly reduces the occurrence of side reactions, leading to a more efficient and sustainable process. The experimental and density functional theory calculations demonstrated that the adsorption of Ph–CH₂OH and Ph–CHO and the generation of electrophilic OH* were promoted due to the unsaturated coordination of the Zn atom in the PtZn-ZnO_x interfaces. Furthermore, the potential-determining step of coupling OH* with Ph–CHO was promoted due to the low energy barrier at the PtZn-ZnO_x interface, leading to improved catalytic activity and selectivity. This study outlines a novel approach to designing highly efficient electrocatalysts for high-efficiency alcohol valorization at low voltages.

Machine learning has boosted the remarkable development of crystal structure prediction (CSP), greatly accelerating modern materials design. However, slow location of the low-energy regions on the potential energy surface (PES) is still a key bottleneck for the overall search efficiency. Here, we develop a low-energy region explorer (LoreX) to rapidly locate low-energy regions on the PES. This achievement stems from graph-deep-learning-based PES slicing, which classifies structures into different prototypes to divide and conquer the PES. The accuracy and efficiency of LoreX are validated on 27 typical compounds, showing that it correctly locates low-energy regions with only 100 selected samples. The powerful capability of LoreX is demonstrated in solving two challenging problems: discovering new boron allotropes and identifying the puzzling crystal structures of the ordered vacancy compound CuIn₅Se₈. This study establishes a new method for rapid PES exploration and offers a highly efficient and generally applicable approach to accelerating CSP.

The fabrication of nanostructures from polycyclic aromatic hydrocarbons (PAHs) is highly attractive owing to their unique optical, electrical, and magnetic properties. However, the creation of uniform and well-defined PAH nanostructures by self-assembly still remains a significant challenge. Herein, we report that highly uniform hexagonal rods can be obtained from triphenylene (TP)-derived monomers by synchronized polymerization and self-assembly (SPSA). These rods have a single-domain columnar liquid crystalline structure in which columns formed from stacked TPs are along the long axis of the rods. The length/diameter ratios of the rods can be tuned over a wide range. Key factors to achieve SPSA of PAHs were analyzed, and the formation mechanism was clarified. In particular, it is observed that successful SPSA occurs below an upper critical temperature, which could be attributed to insufficient microphase separation between the side chains and the main chains and should be a general principle for SPSA. Furthermore, we demonstrate that the columnar stacking of TP units significantly promotes the intersystem crossing of the singlet excited state to the triplet excited state, resulting in simultaneous fluorescence and phosphorescence emission at room temperature. This work may be extended to a wide range of PAHs to regulate their self-assembly and light emission properties.

The hydro/dicarboxylation of ethylene (C₂H₄) feedstock with CO₂ to produce high-value carboxylic acids is an industrially relevant yet challenging reaction due to their extremely low reactivities. Herein, we present an effective strategy to synthesize propionic acid and succinic acid from a mixture of CO₂ and C₂H₄ catalyzed by high-energy water radiolysis. The process involves the generation of CO₂ radical anions via the barrierless attachment of hydrated electrons to CO₂, facilitating an ambient, continuous carboxylation of C₂H₄ with an efficiency of 81.4%. Utilizing easily available electron beam irradiation, we achieved a combined production rate of 0.34 mmol L^–1 min^–1 for carboxylic acids, which is unattainable by the existing methods. Notably, product selectivity between hydro- and dicarboxylation was dose-rate/beam intensity-dependent: high-dose-rate irradiation favored succinic acid formation with a proportional yield of up to 65.4%, while milder conditions resulted in an 85.1% yield of propionic acid. We suggested that the simplicity and efficiency of the present carboxylation approach promote circular carbon in the sustainable chemical industry.

Janus particles, with their intrinsic asymmetry, are attracting major interest in various applications, including emulsion stabilization, micro/nanomotors, imaging, and drug delivery. In this context, Janus polymersomes are particularly attractive for synthetic cell development and drug delivery systems. While they can be achieved by inducing a phase separation within their membrane, their fabrication method remains largely empirical. Here, we propose a rational approach, using Flory–Huggins theory, to predict the self-assembly of amphiphilic block copolymers into asymmetric Janus polymersomes. Our predictions are experimentally validated by forming highly stable Janus giant unilamellar vesicles (JGUVs) with a remarkable yield exceeding 90% obtained from electroformation of various biocompatible block copolymers. We also present a general phase diagram correlating mixing energy with polymersome morphology, offering a valuable tool for JGUV design. These polymersomes can be extruded to achieve quasi-monodisperse vesicles while maintaining their Janus-like morphology, paving the way for their asymmetric functionalization and use as active carriers.

With the increase in greenhouse gas emissions and their detrimental effect on the environment, there is a push to develop a renewable way to produce H₂, a fuel source that has nonharmful byproducts, unlike traditional methods of energy production. Alkaline water electrolysis has seen increasing focus as a viable way to produce H₂, but efficient and stable electrocatalysts are required to facilitate this process. Here, a heterogenized Co(II) phenanthroline-based complex for the production of H₂ from alkaline water is disclosed. Activity was improved by considering the role of axial Co ligation and the reaction environment created by the polymer binder in the catalyst inks by using variable ratios of Nafion and poly-4-vinylpyridine (P4VP). A ratio of 1:1 Nafion:P4VP was found to have the highest stability, and Co nanoparticle formation was not observed when P4VP was included as part of the binder mixture. The activity and stability enhancement could not be replicated by the addition of molecular pyridine or the use of poly-2-vinylpyridine, which is sterically prevented from coordinating to Co. The increased electrochemical performance caused by the inclusion of Nafion as part of the polymer binder is attributed to a role in mass transfer to and from the Co active site during catalysis, complementing the stabilizing effect of P4VP on the molecular active site.

Lipid nanoparticles (LNPs) are widely used for delivering therapeutic nucleic acids, yet the relationship between their internal structure and intracellular behavior, particularly before RNA release, remains unclear. Here, we elucidate how lipid-siRNA organization within LNPs can modulate their intracellular delivery dynamics. We use cryo-electron microscopy and photochemical assays to reveal that increased siRNA loading can reduce helper lipids’ distribution to the LNP surface, while siRNA consistently localizes near the surface. These alterations in lipid-siRNA organization affect LNP membrane fluidity, enhancing LNP fusion with cellular membranes and promoting cytosolic siRNA delivery, primarily via macropinocytosis. Using photosensitive lipids and live cell imaging, we demonstrate that lipid-siRNA organization regulates LNP responsiveness to external stimuli, significantly affecting siRNA endosomal escape efficiency upon light activation. We further confirm this observation using convex lens-induced confinement microscopy and single-particle imaging. Overall, our findings provide critical insights into how lipid-siRNA organization shapes LNP intracellular dynamics, offering rational design principles for optimizing LNP-based RNA therapeutics.

Mechanically interlocked networks (MINs) with dense mechanical bonds can amplify the dynamic behaviors of the mechanical bonds to exhibit decent mechanical properties. Energy dissipation resulting from mechanical bond motion is essential for improving toughness, yet effective strategies to optimize this process remain underexplored. Here, by designing mechanical bond models with controllable mobility, we establish a fortification strategy for the two key factors governing energy dissipation, host–guest recognition and sliding friction, thereby enabling mechanical property enhancement of mechanically interlocked materials. Specifically, the [2]rotaxanes in MIN-1 and MIN-2 exhibit identical axle structures, with MIN-1 incorporating a small benzo-21-crown-7 ring and MIN-2 incorporating a large benzo-24-crown-8 ring. Strain rate-dependent cyclic tensile tests reveal that the energy required to drive mechanical bond motion in MIN-1 and MIN-2 is 510 and 260 kJ/m³, respectively, indicating that the small wheel size enhances host–guest recognition. Furthermore, the apparent activation energy for the sliding motion of the mechanical bonds in MIN-1 (11.0 kJ/mol) is higher than that in MIN-2 (6.70 kJ/mol), suggesting increased sliding friction in MIN-1. Due to these two aspects, MIN-1 exhibits superior energy dissipation performance (damping capacity = 92%) compared to MIN-2 (78%), translating to a higher toughness (7.50 vs 5.70 MJ/m³).

The growth of metal–organic frameworks (MOFs) is most frequently accessed by the direct assembly of metal cations and multitopic ready-to-connect ligands under solvothermal conditions. However, such nonambient conditions are expected to impose a synthetic challenge to incorporate degradable ligands into MOFs. This explains why imine-based MOFs are scarce as the imine motif is usually prone to decompose through hydrolysis. This work not only showcases mechanochemistry as an ambient, sustainable, and high-yield strategy for synthesizing a variety of imine-based MOFs but also achieves the integration of ligand synthesis and MOF growth into a single tandem step. Thus, this work provides straightforward access to imine-based MOFs, a subfamily of historically challenging MOF materials.

Colonic mucus forms a first line of defense against bacterial invasion while providing nutrition to support coinhabiting microbes in the gut. Mucus is composed of polymeric networks of mucin proteins, which are heavily modified post-translationally. The full compendium of enzymes responsible for these modifications and their roles in health and disease remain incompletely understood. Herein, we determine the biochemical function of NXPE1, a gene implicated in ulcerative colitis (UC), and demonstrate that it encodes an acetyltransferase that modifies mucin glycans. Specifically, NXPE1 utilizes acetyl-CoA to regioselectively modify the mucus sialic acid, 5-N-acetylneuraminic acid (Neu5Ac), at the 9-OH group to generate 9-O-acetylated Neu5Ac (Neu5,9Ac₂). We further demonstrate that colonic organoids derived from donors harboring the missense variant NXPE1 G353R, which is protective against UC, exhibit severely impaired acetylation of Neu5Ac on mucins. Together, our findings support a model in which NXPE1 masks the alcohols of mucus sialoglycans via acetylation, which is important for modulating mucus barrier properties that limit interactions with commensal microbes.

Compounds constructed by distorting the ring systems of natural products serve as a ready source of complex and diverse molecules, useful for a variety of applications. Herein is presented the use of the diterpenoids steviol and isosteviol as starting points for the construction of >50 new compounds through this complexity-to-diversity approach, featuring novel ring system distortions and a noteworthy thallium(III) nitrate (TTN)-mediated ring fusion. Evaluation of this collection identified SteviX4 as a potent and selective anticancer compound, inducing cell death at low nanomolar concentrations against some cancer cell lines in culture, compared to micromolar activity against others. SteviX4 induces ferroptotic cell death in susceptible cell lines, and target identification experiments reveal SteviX4 acts as an inhibitor of glutathione peroxidase 4 (GPX4), a critical protein that protects cancer cells against ferroptosis. In its induction of cell death, SteviX4 displays enhanced cell line selectivity relative to most known GPX4 inhibitors. SteviX4 was used to reveal dependency on GPX4 as a vulnerability of certain cancer cell lines, not tied to any one type of cancer, suggesting GPX4 inhibition as a cancer type-agnostic anticancer strategy. With its high fraction of sp³-hybridized carbons and considerable cell line selectivity and potency, SteviX4 is unique among GPX4 inhibitors, serving as an outstanding probe compound and basis for further translational development.

Achieving ultrahigh-color-purity circularly polarized luminescence (CPL) in low-dimensional chiral perovskites is challenging due to strong electron–phonon coupling caused by lead halide octahedral distortion. Herein, the circularly polarized piezoluminescence behaviors of six novel chiral perovskites, (S/R-3-XPEA)₂PbBr₄ (PEA = phenethylamine; X = F, Cl, Br), were systematically investigated. Upon compression, (S/R-3-ClPEA)₂PbBr₄ exhibits significant piezofluorochromic behaviors, transforming from yellow CPL to ultrahigh-color-purity deep-blue CPL. At 2.5 GPa, the deep-blue CPL intensity increases by an order of magnitude and its luminescence asymmetry factors (g_lum) are amplified from the initial ±0.03 to ±0.1. (S/R-3-BrPEA)₂PbBr₄ presents a similar piezochromic response, realizing deep-blue CPL at 1.7 GPa, while (S/R-3-FPEA)₂PbBr₄ retains a yellow CPL under high pressure. High-pressure structural characterization and theoretical calculations confirm that pressure-enhanced halogen bonds reduce the penetration depth of S/R-3-BrPEA⁺ and S/R-3-ClPEA⁺ into the [PbBr₆]^4– frameworks, significantly suppressing electron–phonon coupling and increasing magnetic transition dipole moment in (S/R-3-BrPEA)₂PbBr₄ and (S/R-3-ClPEA)₂PbBr₄, which are responsible for the ultrahigh-purity deep-blue CPL and chirality amplification, respectively.

Despite the significant potential of photocatalysis as a robust synthetic tool, the high reactivity of radicals often presents challenges in achieving optimal chemoselectivity. In this study, we demonstrate that this inherent limitation can be strategically harnessed for asymmetric photoredox catalysis. By utilizing a chiral catalyst to facilitate kinetic resolution between the two enantiomers of racemic radical intermediates, one enantiomer selectively undergoes the desired transformation, while noncatalytic side reactions deplete the other enantiomer. Consequently, an attractive asymmetric photoredox three-component Minisci-type reaction involving bromides, racemic homoallylic tertiary alcohols or amines, and azaarenes has been developed. This approach enables efficient assembly of tertiary alcohols and amines onto the nonadjacent β-position of an azaarene-functionalized tertiary carbon stereogenic center with high levels of enantio- and diastereoselectivity. Therefore, this method not only allows for direct utilization of readily available racemic feedstocks that are challenging to convert into prochiral radicals via redox processes but also provides an efficient strategy for synthesizing complex molecules with multiple stereocenters.

The synthesis of enantiopure and structurally unique spiro-type molecules is of utmost significance in catalysis, synthetic chemistry, and related fields. We present here a general solution, a nickel-catalyzed [2 + 2 + 2] cycloaddition, for accessing enantioenriched spiropyridines from readily available nitriles and alkynes in a single synthetic step, including (1) enantio-relay double [2 + 2 + 2] cycloaddition of malononitriles with alkynes and (2) kinetic resolution [2 + 2 + 2] cycloaddition of racemic pyridine-containing nitriles with alkynes. Both strategies feature a broad substrate scope and exclusive regioselectivities, and are scalable to multigram. Remarkably, the double [2 + 2 + 2] cycloaddition integrates enantio-induction by desymmetrizing dinitriles during the initial catalytic cycle with additional enantio-enhancement during the second cycloaddition (enantio-relay), yielding excellent enantioselectivities (>99% ee for all examined examples). Furthermore, the highly efficient kinetic resolution strategy enables the achievement of exceptionally high enantioselectivities without compromising yields (s > 200 for most examples), overcoming the general challenges of kinetic resolution toward yield and enantioselectivity. The ability to construct previously inaccessible spiro structures lays the groundwork for advancing spiropyridine derivatives, especially the multinitrogen-containing compounds as potential ligands. Due to the perpendicular molecular orientation and inherent rigidity of the architectures obtained, we anticipate significant promise of the presented synthetic approaches for enhancing efforts in synthesis and catalysis.

Emerging evidence indicates that lipid droplets (LDs) play important roles in lipid metabolism, energy homeostasis, and cell stress management. Notably, dysregulation of LDs is tightly linked to numerous diseases, including lipodystrophies, cancer, obesity, atherosclerosis, and others. The pivotal physiological roles of LDs have led to an exploration of research in recent years. The functions of LDs are inherently connected to the composition of their proteome. Current methods for profiling LD proteins mostly utilize LD fractionation, including those based on proximity-based labeling techniques. Global profiling of the LD proteome in live cells without the isolation of LDs is still challenging. Herein, we disclose two small-molecule chemical probes, termed LDF and LDPL. Both LDF/LDPL are small in size and could freely and specifically migrate within the lipid context of LDs. Consequently, they were successfully used for live-cell fluorescence imaging of LDs and from animal tissues. We further showed that LDPL was capable of large-scale profiling of the LD proteome without the need of LD isolation. By using LDPL, 1584 high-confidence proteins, most of which could be annotated to prominent LD functions, were next identified. Importantly, further validation studies by using representative “hit” proteins revealed that CHMP6 and PRDX4 could act as the lipophagy receptor and lipolysis suppressor, respectively. Our results thus confirmed for the first time that LDPL is a powerful chemical tool for in situ profiling of LD proteomes. With the ability to provide a deeper understanding of LD proteomics from the native cellular environments, our newly developed strategy may be used in future to decipher the dynamics and molecular mechanism of LDs in various diseases.

The homogeneous catalytic functionalization of methane is extremely challenging due to the relative nonpolarity and high C–H bond strength of this hydrocarbon. Here, using catalytic quantities (10 mol %) of CpMn(CO)₃ or Cp*Re(CO)₃, the conversion of methane and benzene C–H bonds to C–Be and H–Be bonds by CpBeBeCp has been achieved under photochemical conditions. Possible intermediates in the beryllation reactions─trans-bis(beryllyl)-manganese and -rhenium complexes─were also isolated. Quantum chemical calculations indicate that the inherent properties of the beryllyl ligands─which are powerfully σ-donating and feature highly Lewis acidic beryllium centers─are decisive in enabling methane functionalization by these systems.

The dynamics of chemical reactions in solution are of paramount importance in fields ranging from biology to materials science. Because the hydrogen-bond network and proton dynamics govern the behavior of aqueous solutions, they have been the subject of numerous studies over the years. Here, we report the observation of a previously unknown associative state in the hydroxide ion that forms when a proton from a neighboring water molecule approaches the hydroxide ion, utilizing resonant inelastic soft X-ray scattering (RIXS) and quantum dynamical simulations. State-of-the-art theoretical analysis reveals state mixing in the electronically excited states between aqueous hydroxide ions and the solvent. Our results give new insights into chemical bonding and excited-state dynamics in the aqueous environment. This investigation of associative states opens up new pathways for spectroscopic studies of chemical reaction dynamics and lays the foundation for directly accessing dynamic proton exchange in solution.

Organic polymers generally feature 1-dimensional chains or 2-dimensional rings in their backbones since synthetic challenges limit the availability of 3-dimensional monomers. Inorganic cages are less strained and more accessible, offering an alternative route to explore this parameter space. However, only two families─carboranes and polyhedral oligomeric silsesquioxanes (POSS)─have been well-studied, revealing materials with valuable mechanical and thermal properties. Further exploration of this frontier requires the development of new inorganic cages that are accessible, stable, and polymerizable. Here we report that an easily assembled, bench-stable PN cage, P(NMeNMe)₃P, undergoes Staudinger polycondensation with organic diazides to yield robust, solution-processable, and film-forming linear poly(trihydrazino-diphosphine diazide)s─PHPDs─as a new family of hybrid organic–inorganic polymers. Their solubility can be controlled by diazide choice and backbone architecture, which we rationally modify to access alternating or multiblock copolymers. We also show how a tetraphosphorus cage, P₄(NMe)₆, can be used to cross-link PHPDs. The T_g values for PHPDs are comparable to those of rigid π-conjugated polymers (>150 °C), and, despite a high nitrogen content (up to 32%) and three N–N σ-bonds per repeat unit, they show decomposition temperatures >200 °C with char yields up to 60%. These data support hypotheses of high stability arising from the presence of 3-dimensional backbone units. We further show that PHPDs may be leveraged for halogen-free flame retardancy. Collectively, the results debut new low-carbon polymers with an unusual backbone topology, reveal the design rules for controlling their microstructures and properties, and lay the foundation for future applied studies.

Monoacylglycerol lipase (MAGL) is the pivotal catabolic enzyme responsible for signal termination in the endocannabinoid system. Inhibition of MAGL offers unique advantages over the direct activation of cannabinoid receptors in treating cancer, metabolic disorders, and inflammatory diseases. Although specific fluorescent molecular imaging probes are commonly used for the real-time analysis of the localization and distribution of drug targets in cells, they are almost invariably composed of a linker connecting the pharmacophore with a large fluorophore. In this study, we have developed miniaturized fluorescent probes targeting MAGL by incorporating a highly fluorescent boron-dipyrromethene (BODIPY) moiety into the inhibitor structure that interacts with the MAGL active site. These miniaturized fluorescent probes exhibit favorable drug-like properties such as high solubility and permeability, picomolar potency for MAGL across various species, and high cell selectivity and specificity. A range of translational investigations were conducted, including cell-free fluorescence polarization assays, fluorescence-activated cell sorting analysis, and confocal fluorescence microscopy of live cancer cells, live primary neurons, and human-induced pluripotent stem cell-derived brain organoids. Furthermore, the application of red-shifted analogs or ¹⁸F positron emission labeling illustrated the significant versatility and adaptability of the fluorescent ligands in various experimental contexts.

Biological nanopore technology has emerged as a promising tool for analyzing peptides and post-translational modifications at the single-molecule level. However, a broader application is currently limited by the partial separation of peptides and low-throughput, mainly due to the nonuniform peptide signals detected by nanopores. Narrowing the peptide signal distribution is crucial for improving the nanopore’s sensing ability but remains a bottleneck. Here, we demonstrate that capturing peptides with electrophoretic force against electroosmotic flow can provoke more uniform blockades in α-hemolysin nanopores. By using buffers with 2 M KCl at pH 3.8, we obtain the most uniform peptide signals, which may be correlated to the shape, linearization, and actual dwelling position of peptides. Five peptides with acetylation and phosphorylation, including isomeric peptides, can be readily separated from each other. The citrullination replacement of arginine and the β-hydroxybutyrylation modification in another peptide sequence are also discriminated in a mixture. A series of peptides with different compositions induced uniform peptide blockades when they were analyzed with our method. Our work presents an efficient approach to optimize nanopore signals for peptide analysis using α-hemolysin nanopores.

The rapid emergency and spread of antimicrobial-resistant (AMR) bacteria and the lack of new antibiotics being developed pose serious threats to the global healthcare system. Therefore, the development of more effective therapies to overcome AMR is highly desirable. Metal ions have a long history of serving as antimicrobial agents, and metal-based compounds are now attracting more interest from scientific communities in the fight against AMR owing to their unique mechanism. Moreover, they may also serve as antibiotic adjuvants to enhance the efficacy of clinically used antibiotics. In this perspective, we highlight important showcase studies in the last 10 years on the development of metal-based strategies to overcome the AMR crisis. Specifically, we categorize these metallo-antimicrobials into five classes based on their modes of action (i.e., metallo-enzymes and metal-binding enzyme inhibitors, membrane perturbants, uptake/efflux system inhibitors/regulators, persisters inhibitors, and oxidative stress inducers). The significant advantages of metallo-antimicrobials over traditional antibiotics lie in their multitargeted mechanisms, which render less likelihood to generate resistance. However, we notice that such modes of action of metallo-antimicrobials may also raise concern over their potential side effects owing to the low selectivity toward pathogens and host, which appears to be the biggest obstacle for downstream translational research. We anticipate that combination therapy through repurposing (metallo)drugs with antibiotics and the optimization of their absorption route through formulation to achieve a target-oriented delivery will be a powerful way to combat AMR. Despite significant challenges, metallo-antimicrobials hold great opportunities for the therapeutic intervention of infection by resistant bacteria.

The electrocatalytic utilization of oxidized nitrogen waste for C–N coupling chemistry is an exciting research area with great potential to be adopted as a sustainable method for generation of organonitrogen molecules. The most widely used C–N coupling reaction is reductive amination. In this work, we develop an alternative electrochemical reductive amination reaction that can proceed in neutral aqueous electrolyte with nitrite as the nitrogenous reactant and via an oxime intermediate. We develop a selection criterion for nitrite reduction electrocatalysts suited for oxime electrosynthesis and, in doing so, find Pd to be a highly efficient catalyst for this reaction, reaching an oxime Faradaic efficiency of 82% at −0.21 V vs the reversible hydrogen electrode. The aliphatic or aromatic structure of the carbonyl reactant impacts the efficacy of the catalyst, with aromatic substrates leading to suppressed oxime formation and detrimental reduction of the carbonyl to the alcohol. We developed a Pb/PbO electrocatalyst that selectively performs oxime reduction in the neutral aqueous electrolyte. With acetone as a model substrate, we demonstrate an efficient one-pot, two-step electrochemical reaction for the conversion of acetone to isopropyl amine with 85% yield and 50% global Faradaic efficiency.

Gene-targeted therapies are revolutionizing cancer treatment due to their high specificity and low toxicity. Among these, ribozymes hold promise as independent gene therapy agents capable of directly cleaving target mRNAs. The pistol ribozyme, discovered in 2015, stands out for its compact structure and robust cleavage activity, making it a promising candidate for RNA silencing under physiological conditions. However, its clinical application is limited by nuclease susceptibility and biological barrier penetration. To overcome these obstacles, this study presents an innovative gene-regulation strategy incorporating engineered pistol ribozymes into a spherical nucleic acid (SNA) nanocarrier. This catalytic SNA nanocarrier, built on a DNA core–shell framework, combines the ribozyme with doxorubicin (Dox) to form the ApRz-CS/Dox nanoplatform. The design of ApRz-CS/Dox features a homopolymerized DNA core and a reticular DNA shell, enhancing stability. Tumor-targeting aptamers are arranged on its surface, directing it specifically to cancer cells. Within the target cells, the ribozyme is released in response to overexpressed miR-21, facilitating the cleavage of polo-like kinase 1 mRNA. This integrated approach effectively combines gene therapy with the chemotherapeutic effects of Dox, addressing the challenges associated with the delivery of newly developed nucleic acid drugs and offering a promising strategy for enhanced cancer treatment.

Glioblastoma (GBM) has limited treatment options, as the restrictive blood–brain barrier (BBB) prevents most therapeutics from accumulating at sufficient levels in the brain. Convection-enhanced delivery (CED) offers a method for administering therapeutics directly into brain tumor tissue, but free drugs can be cleared rapidly and may be toxic to off-target cells. Drug-loaded nanoparticles (NPs) are a promising platform to prolong the residence time and improve cellular targeting of therapeutics. We designed drug-conjugated NPs comprising a liposomal core modified with a layer-by-layer (LbL) polymer coating to promote tumor penetration, retention, and tumor-selective cellular association. Covalent conjugation of the potent microtubule inhibitor monomethyl auristatin-F (MMAF) to lipid headgroups resulted in striking potency against a range of patient-derived GBM cell lines compared to free MMAF and outperformed an EGFR-targeted antibody–drug conjugate of MMAF under clinical investigation. In vivo, a single CED infusion of LbL-functionalized MMAF NPs in orthotopic GBM-bearing mice displayed improved distribution and retention of both the NPs and the MMAF payload within the tumor. The LbL coating promotes selective uptake by GBM cells and prolongs drug retention, overcoming limitations of rapid clearance associated with traditional CED approaches. This treatment inhibited tumor progression and significantly extended survival compared to free MMAF, MMAF-conjugated liposomes, and an EGFR-MMAF antibody–drug conjugate. This NP platform offers a promising strategy for enhancing local GBM therapy by improving drug exposure within tumors while minimizing systemic toxicity.

The complex charge storage mechanisms in aqueous MnO₂-based supercapacitors have posed significant challenges to a comprehensive understanding of their chemical behavior. In this study, we employed Au-core@MnO₂-shell nanoparticle-enhanced Raman spectroscopy, alongside electrochemical analysis and X-ray absorption, to systematically investigate the competitive charge storage chemistry of protons and cations within the inner and outer layers of δ-MnO₂ under alkaline conditions. Our findings reveal that δ-MnO₂ operates through a dual mechanism: the intercalation and deintercalation of metal cations dominate charge storage in the inner layer, while surface chemisorption of protons governs the outer layer. Notably, cation insertion induces an irreversible phase transition from MnO₂ to Mn₂O₃, whereas the surface redox process involves a reversible transformation among MnO₂, MnOOH, and Mn(OH)₂. Additionally, spectral evidence, supported by ab initio molecular dynamics simulations, elucidates the structural changes of interfacial water associated with proton-mediated charge storage in the outer layer. Electrochemical analysis further demonstrates that surface charge storage, primarily mediated by a proton-coupled electron transfer mechanism, is the dominant contributor to the overall capacitance. This work not only advances the molecular-level understanding of electrochemical processes in MnO₂-based supercapacitors but also highlights the potential for optimizing surface proton-coupled electron transfer mechanisms to enhance capacitive performance.

Profiling multiple enzymatic activities in tissue is crucial for understanding complex metabolic and signaling networks, yet remains a challenge with existing optical microscopies. Here, we developed a Fenton-promoted luminol electrochemiluminescence (ECL) imaging method to achieve the spatial mapping of multiple enzymatic activities within a single tissue section. This method quantitatively visualizes individual enzymatic activity by combining the enzymatic conversion of substrates with the chemical confinement of the locally produced hydrogen peroxide. To achieve high-resolution spatial imaging by limiting the diffusion (∼500 μm) of hydrogen peroxide, iron oxide nanoparticles were coated on the tissue surface to initiate the Fenton process, locally converting hydrogen peroxide into short-lived hydroxyl radicals with a nanometer-scale diffusion range. The Fenton-promoted ECL emission is confined at the enzymatic conversion sites, offering unprecedented spatial visualization of four tumor-associated oxidases within a single tissue section. Colocalization revealed a synergistic effect between lysyl oxidase and quiescin sulfhydryl oxidase on post-translational modifications of tumor extracellular matrix proteins, along with a previously undiscovered interaction with amiloride-sensitive amine oxidase, which could not be distinguished based on expressions or single enzymatic activity alone. This approach offers a novel activity-based protein profiling tool at the tissue level, providing new data for future enzynomic research and multimodal imaging.

The ability to arrange brightly fluorescent nanoscale materials into well-defined patterns is critically important in advanced optoelectronic structures. Traditional methods for doing so generally involve depositing different color quantum dot “inks,” irradiating reactive (e.g., cross-linkable) ligands at their surface, and then lifting off the unexposed sections in a developer solvent. Here, we outline a fundamentally different approach for directly patterning the emission color of nanocomposite thin films utilizing mask-based lithographic techniques and laser scanning methods. In this system, a polymer film containing cesium lead halide nanocrystals (NCs) is embedded with an organohalide─termed a “photohalide generator”─which undergoes a light-triggered, perovskite-catalyzed reduction and release of halide anion for uptake by the NC lattice, markedly shifting its band gap. In this manner, a blue emitting (CsPbBr_1.5Cl_1.5) film becomes green and/or red in the exposed areas of a photomask, replicating the mask features as a multichromatic array (e.g., green, red, etc. colors against a blue background). The resolution limits of this materials system were probed using laser scanning tools capable of writing intricate patterns with feature sizes approaching a single micron─more than an order of magnitude smaller than the most comparable methods based on inkjet printing. Lastly, these methods are extended to a combined shape and color patterning process for making free-standing filamentous structures with striped and alternating fluorescence emission along their length.

While nucleic-acid-based cancer vaccines hold therapeutic potential, their limited immunogenicity remains a challenge due in part to the low efficiency of cytoplasmic delivery caused by lysosomal entrapment. In this work, we found that plasmids encoding both an antigen and a STING agonist protein adjuvant can self-assemble into coordination nanofibers, triggered by manganese ions. We developed a strategy to construct a DNA vaccine, termed MnO₂-OVA-CDA-mem, formed by the coencapsulation of manganese dioxide (MnO₂), an antigen-expressing plasmid (encoding ovalbumin, OVA), and an adjuvant enzyme-expressing plasmid (encoding STING agonist, CDA) within dendritic cell (DC) membranes. Upon uptake into acidic lysosomes, Mn²⁺ released from MnO₂ triggered the nucleic acids to undergo a morphological change from nanospheres (∼180 nm diameter) to nanofibers (∼1 μm length), resulting in an increase in mechanical strength by about 9-fold and consequently lysosomal membrane disruption. The antigen OVA and adjuvants Mn²⁺ and CDA in the cytoplasm triggered strong DC activation and antigen-specific CD8⁺ T cell metalloimmune responses, significantly inhibiting the growth of B16-OVA tumors and inducing long-term immune memory. Altogether, MnO₂-OVA-CDA-mem holds potential as a platform for nucleic acid antigen and adjuvant delivery using an in situ self-assembly strategy in a metal-driven, stimulus-responsive, and programmable manner for cancer metalloimmunotherapy.

Proteolysis targeting chimera (PROTAC)-based degraders are highly potent pseudocatalytic drugs, but on-target off-site homing could yield undesirable consequences. We report here a generalizable AND-logic gated PROTAC, where the concurrent presence of two different disease-relevant endogenous stimuli liberates an active protein degrader. We design Dual-Action-Only PROTAC (DAO-PROTAC) molecules that are dormant and can only be activated in the presence of both hypoxia and cathepsin-L to degrade the protein of interest (POI). We also show that the dormancy of DAO-PROTACs translates to considerable mitigation of cytotoxicity, demonstrating the potential advantages over the corresponding free PROTAC and single-stimulus triggerable pro-PROTACs.

The family of Cephalotaxus diterpenoids represents a captivating class of natural products that are of significant interest from both structural and biological perspectives within our community. Here we wish to report a 15-step, enantioselective total synthesis of the Cephalotaxus diterpenoid fortalpinoid Q. Our approach highlights (1) a Jacobsen’s catalytic enantioselective Claisen rearrangement that enabled the single-step formation of two vicinal stereogenic centers, including an all-carbon quaternary center; (2) a mild, oxoammonium salt (TEMPO⁺BF₄^–)-promoted dehydrative Nazarov cyclization that swiftly forged the crucial cyclopentadiene moiety via an unfunctionalized tertiary divinyl carbinol (TDC) substrate; and (3) a facile aldol-lactonization cascade that ultimately resolved the last obstacle in the synthesis.

Nitroso compounds, R-N═O, containing N═O double bonds are ubiquitous and widely utilized in organic synthesis. In contrast, heavier congeners of nitroso compounds, namely pnictinidene chalcogenides R-Pn = E (Pn = P, As, Sb, Bi; E = O, S, Se, Te), are highly reactive and scarce. They have been stabilized in the coordination sphere of Lewis acid/base or by pronounced contribution from resonance structures, whereas free species with unperturbed pnictogen-chalcogen double bonds remains elusive. In this work, we report the isolation and characterization of arylstibinidene chalcogenides, which are the first heavier congeners of aromatic nitroso compounds. They are facilely synthesized through the salt metathesis reactions of aryldichlorostibane and dilithium chalcogenides. They bear unperturbed Sb═E (E = S, Se and Te) double bonds due to poor orbital overlap between the C 2p orbitals of the phenyl ring of the substituent and the Sb 5p orbitals. Moreover, they show versatile reactivity, including acting as chalcogen atom transfer reagents and reacting with small molecules via (cyclo)addition.

The importance of crystal surface reactivity of reticular materials is exemplified by exfoliation of nonporous layered zeolitic imidazolate framework Zn(mIm)₂·0.5mImH (ZIF-L, mImH = 2-methylimidazole). Sonication of ZIF-L ethanolic suspensions leads to exfoliation of microcrystals along the 2 0 0 planes, giving rise to 1.5 μm wide × 25 nm thick flakes, which we term ZIF-L_exf. ZIF-L_exf exhibits a high reactivity toward hydrolytic degradation of extremely toxic G-type nerve agents, Soman (GD), and simulant diisopropylfluorophosphate (DIFP). The reactivity of the crystal surface of ZIF-L_exf toward P–F bond breakdown gives rise to framework structural degradation, releasing nucleophilic mImH molecules that reactivate organophosphate-inhibited acetylcholinesterase within 10 min. This detoxification process can be taken as a proof of concept for reversing organophosphorous poisoning. More generally, this approach underscores the importance of the crystal surface nature and composition to control the reactivity of reticular materials.

(+)-Saxitoxin, a potent neurotoxin and Na_V blocker, poses significant synthetic challenges due to its compact tricyclic framework and guanidinium moieties. We report a concise and asymmetric total synthesis featuring an intramolecular [2 + 2] photocycloaddition of an alkenylboronate ester equipped with a new chiral auxiliary. This auxiliary, compatible with UV light and easily exchangeable on B(pin) derivatives, enabled high stereocontrol through hydrogen-bond-mediated transition-state stabilization. Our approach not only introduces an innovative surrogate for intramolecular Michael addition, particularly addressing transformations with contra-thermodynamic barriers, but also highlights the potential of boron-enabled photochemistry for synthesizing complex molecules.