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  • Biomolecular condensates mediate C-N bond formation NATURE CHEMICAL BIOLOGY Song, X., Ma, Y., Chen, M. W., Yu, W., Yan, X., Xu, J., Lyu, L., Hyman, A. A., Dai, Y., Zare, R. N. 2026

    Abstract

    We discover that biomolecular condensates, formed by intrinsically disordered proteins without inherent chemical activity, can spontaneously drive nonenzymatic reductive amination. These condensates facilitate reactions between amines and aldehydes or ketones, yielding imines, which are subsequently hydrogenated to form alkylated amines leading to C-N bond formation. Our experiments show that condensates modulate the reductive amination of diverse types of metabolite containing carbonyl groups. Using combinatorial metabolomics, we found that condensates generate previously unknown metabolites through the dimerization of natural amines with ketones and aldehydes. Metabolomics in living cells confirms that the ability of condensates in mediating C-N bond formation enables the synthesis of new metabolites and regulates cellular pathways. These findings uncover a previously unrecognized inherent function of biomolecular condensates, redefining their roles in metabolism. This further highlights the broader influence of condensates on chemical homeostasis and biochemical regulation in biological and prebiotic chemistry.

    View details for DOI 10.1038/s41589-026-02169-2

    View details for Web of Science ID 001722999000001

    View details for PubMedID 41882384

    View details for PubMedCentralID 10715172

  • Mapping Cell Metabolic States by Image-Enabled Gating Metabolomic Cytometry. Analytical chemistry He, Y., Ren, Z., Chen, X., Lyu, L., Liu, Z., He, W., Zheng, X., Huang, G. 2026

    Abstract

    Cell atlases can reveal cell heterogeneity within tissues, which are inherently complex biological samples. While high-throughput single-cell metabolomics has been reported, single-cell metabolic atlases are difficult to generate without accurate single-cell signal capture. Here, we describe CyMeta-ImaGating, metabolomic cytometry with an image-enabled gating strategy, for generating single-cell metabolic atlases with verified single-cell profiles from complex samples. These verified profiles are obtained by matching metabolomic profiles with brightfield single-cell images, a process termed image-enabled gating. In scraped HeLa cell suspensions, which contained abundant debris and cellular aggregates, the image-enabled gating strategy increased the proportion of single-cell profiles from 28% to 91-100%. Using CyMeta-ImaGating, we generated spleen cell atlases that distinguished major immune cell types (B, T, and NK cells) and revealed transitions of metabolic states after pathogen activation. We also characterized doxorubicin's effects using liver and cancer cell atlases to illustrate drug specificity: the liver cell atlas revealed specific metabolic states (e.g., arginine upregulation) during drug-induced apoptosis, while the cancer cell atlas showed that drug-responsive metabolic states remained robust despite reduced single-cell rate at high concentrations. These results demonstrate the single-cell metabolic atlas as a critical tool for resolving cell metabolic states and dynamics.

    View details for DOI 10.1021/acs.analchem.5c04091

    View details for PubMedID 41872037

  • Biomolecular Condensates Power Nitrogen Cycling via Concurrent Redox Activities. Journal of the American Chemical Society Song, X., Lyu, L., Li, C., Ma, Y., Zhou, Y., Dai, Y., Zare, R. N. 2026

    Abstract

    The role of the inherent chemical activities of biomolecular condensates in metabolism remains underexplored. We discovered that biomolecular condensates, the constituents of which do not possess any intrinsic enzymatic activities, can modulate the nitrogen cycle composed of nitrate (NO3-), ammonia (NH3), and nitric oxide (NO·). By developing a single-condensate-based mass spectrometry technique, we observed condensate-dependent interconversion between NO3- and NH4+ with externally supplied nitrogen sources. Surprisingly, through mass-spectrometry-based protein analysis and fluorogenic reaction assays, we found that the autoxidation of the arginine residue on the disordered protein could also directly contribute to the released NO·, an important signaling factor in biological systems. This work expands our understanding about the intrinsic reactivity of biomolecular condensates, providing insight into its fundamental impact on nitrogen metabolism as a nitrogen supplier and regulator.

    View details for DOI 10.1021/jacs.5c22593

    View details for PubMedID 41782387

  • Dark Reactions in Microdroplets Explain Widespread Artifacts in Metabolomic Profiling ACS MEASUREMENT SCIENCE AU Song, X., Xu, J., Sun, C., Lyu, L., Kui, H., Zhang, R., Abliz, Z., Zare, R. N. 2026

    View details for DOI 10.1021/acsmeasuresciau.5c00146

    View details for Web of Science ID 001668749500001

  • Comment on "An Alternative Explanation for Ions Put Forth as Evidence for Abundant Hydroxyl Radicals Formed Due to the Intrinsic Electric Field at the Surface of Water Droplets". Analytical chemistry Xu, J., Song, X., Lyu, L., Zhang, X., Zare, R. N. 2025

    View details for DOI 10.1021/acs.analchem.5c04123

    View details for PubMedID 41474784

  • Intrinsic Electric Field Triggers Phenol Oxidative Degradation at Microbubble Interfaces. Journal of the American Chemical Society Xu, J., Song, X., Lu, Y., Lyu, L., Basheer, C., Zare, R. N. 2025

    Abstract

    Phenol, recognized for its environmental persistence and toxicity, typically necessitates high-energy or costly catalytic methods for its removal from industrial wastewater. In this study, we demonstrate the oxidative degradation of phenol at air-water interfaces (AWIs) by microbubbling air through water. High-resolution mass spectrometry revealed the transformation of phenol into progressively oxidized intermediates and ultimately into acetic acid, with a degradation rate of over 96% after 3 h for a 2 mM phenol solution. Complementary vortex experiments constructed a detailed degradation pathway involving sequential hydroxylation, dehydrogenation, and ring-cleavage processes. Radical scavenger experiments and DFT calculations indicate that the mechanism may follow an interfacial electric field-induced excitation pathway via radical reactions. The oxidation trend of para-halogenated phenols (F < Cl < Br < (H) < I) aligns with each radical's HOMO-LUMO gap, supporting the interfacial field-induced molecular activation mechanism. Compared to conventional advanced oxidation processes, our method offers reagent-free operation, reduced secondary pollution, and high efficiency under mild conditions. These findings highlight the AWI-mediated oxidation as a sustainable strategy for degrading phenolic pollutants in water.

    View details for DOI 10.1021/jacs.5c16083

    View details for PubMedID 41452594

  • Anion-π interaction-induced phase separation as a prebiotic pathway to oxygenation. Proceedings of the National Academy of Sciences of the United States of America Ren, X., Song, X., Lyu, L., Chen, M. W., Zare, R. N., Dai, Y. 2025; 122 (39): e2508804122

    Abstract

    Compartmentalization and chemical reactivity serve as the key elements driving prebiotic chemistry for evolution and selection. However, the potential coupling of compartmentalization chemistry with the intrinsic chemical activity of prebiotic compartments remains largely unexplored. Here, we demonstrate that anion-π interactions, which are largely overlooked in the chemistry of phase transition, can drive the formation of micron-sized assemblies. These structures further recruit cations to form anion-π-cation triads. Such assemblies mediate spontaneous oxygenation reactions through their electrochemical environments. This process provides a plausible prebiotic pathway for bioenergetics and molecular oxygen generation on early Earth, leading to the formation of primitive pigments via the oxidation of small molecules and the nontemplated selection of protocells through oxidation-dependent lipid degradation. Our findings highlight a simple yet functionally significant noncovalent interaction that introduces chemical functions into self-assembly and phase transition chemistry, delivering generalizable principles for engineering electrochemically active supramolecular assemblies and a conceptual framework in understanding abiotic evolution and selection.

    View details for DOI 10.1073/pnas.2508804122

    View details for PubMedID 40991438

  • Nondestructive Metabolic Monitoring of Living Organisms by Water-Droplet Extraction and Contact-Free Electrospray Ionization Mass Spectrometry. Analytical chemistry He, Y., Chen, X., Lyu, L., Zare, R. N., Huang, G. 2025

    Abstract

    We present a novel tool for nondestructive in vivo metabolite analysis, which we call MetaTube. This method utilizes a high voltage to facilitate efficient ionization while maintaining electrical isolation from living tissues that are sampled. MetaTube achieves a 2-3 order of magnitude improvement in metabolite signal intensity, giving MetaTube the capacity to identify 10-fold more metabolites. These capabilities allow us to profile metabolites of human skin surfaces and monitor metabolite fluctuations of growing bacterial colonies. MetaTube offers a promising strategy to understand in vivo metabolic dynamics and evaluate the metabolic state of living tissues in real time.

    View details for DOI 10.1021/acs.analchem.5c01018

    View details for PubMedID 40419863

  • Clarifying the Identity of the m/z 36 Ion in Water Microdroplet Mass Spectra. The journal of physical chemistry. A Song, X., Lyu, L., Xu, J., Xing, D., Zhang, X., Zare, R. N. 2025

    Abstract

    Several lines of evidence are presented that when ultrapure water is sprayed into air and the resulting water microdroplets are mass analyzed a peak at m/z 36 appears, which is identified as the water dimer cation. The water dimer cation, (H2O)2+•, and the hydrated ammonium cation, NH4+·H2O, have essentially indistinguishable mass differences in a low-resolution mass spectrum. By comparing the behavior of (H2O)2+• and NH4+·H2O with temperature and salt concentration, we can rule out the formation of NH4+·H2O in the spraying of ultrapure water into laboratory air.

    View details for DOI 10.1021/acs.jpca.5c02557

    View details for PubMedID 40360455

https://orcid.org/0009-0009-0599-700X