{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T03:50:39Z","timestamp":1791949839696,"version":"4.3.4"},"reference-count":39,"publisher":"American Chemical Society (ACS)","issue":"29","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100007219","name":"Natural Science Foundation of Shanghai Municipality","doi-asserted-by":"publisher","award":["21934001"],"award-info":[{"award-number":["21934001"]}],"id":[{"id":"10.13039\/100007219","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007219","name":"Natural Science Foundation of Shanghai Municipality","doi-asserted-by":"publisher","award":["25ZR1401018"],"award-info":[{"award-number":["25ZR1401018"]}],"id":[{"id":"10.13039\/100007219","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22374028"],"award-info":[{"award-number":["22374028"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Metabolites packaged within extracellular vesicles (EVs) are increasingly recognized for their role in intercellular communication and metabolic regulation. However, their comprehensive characterization remains challenging due to the low abundance of metabolites in EVs, interference from complex biological matrixes, and poor ionization efficiency of certain metabolite classes. Here, we developed a membrane-fusion-assisted laser desorption\/ionization mass spectrometry (MF-LDI-MS) strategy for in situ profiling of EV-associated metabolites. The MF-LDI-MS utilizes liposome-coated gold nanoparticles (Lipo@Au NPs) composed of a Au NP core and a cationic lipid bilayer shell. Driven by electrostatic interactions, the cationic liposomes fuse with the negatively charged EV membranes, enabling effective delivery of Au NPs into EVs. The internalized Lipo@Au NPs not only modulate EV sedimentation, facilitating enrichment under mild centrifugation, but also serve as inorganic matrixes for direct LDI-MS detection of retained metabolites within intact EVs. This integrative approach eliminates many of the aforementioned limitations by allowing direct, enrichment-free, and matrix interference-free metabolite analysis while maintaining EV integrity. Combining machine learning, the MF-LDI-MS successfully discriminated pancreatic cancer (PC) patients from healthy controls (HCs) in a cohort of 144 plasma samples, achieving a diagnostic accuracy of 92.1% and identifying nine metabolites as potential biomarkers, demonstrating its applicability to metabolic-level liquid biopsy.<\/jats:p>","DOI":"10.1021\/acs.analchem.6c04341","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T09:23:53Z","timestamp":1784193833000},"page":"21935-21943","source":"Crossref","is-referenced-by-count":1,"title":["Membrane Fusion-Assisted Laser Desorption\/Ionization\nMass Spectrometry for In Situ Extracellular Vesicle Metabolic Fingerprinting"],"prefix":"10.1021","volume":"98","author":[{"given":"Qian","family":"Shi","sequence":"first","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, China, 200433"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuerong","family":"Tang","sequence":"additional","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, China, 200433"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haonan","family":"Yang","sequence":"additional","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, China, 200433"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuedong","family":"Huang","sequence":"additional","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, China, 200433"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4583-0043","authenticated-orcid":true,"given":"Xiaoni","family":"Fang","sequence":"additional","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, China, 200433"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0660-8610","authenticated-orcid":true,"given":"Baohong","family":"Liu","sequence":"additional","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, China, 200433"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"issue":"4","key":"2026072808065908100_cit1","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1038\/nrm.2017.125","article-title":"Shedding light on the\ncell biology of extracellular vesicles","volume":"19","author":"van Niel","year":"2018","journal-title":"Nat.\nRev. Mol. Cell Biol."},{"issue":"1","key":"2026072808065908100_cit2","doi-asserted-by":"publisher","DOI":"10.1038\/s43586-023-00240-z","article-title":"Extracellular vesicle analysis","volume":"3","author":"Hendrix","year":"2023","journal-title":"Nat. Rev. Methods Primers"},{"issue":"6","key":"2026072808065908100_cit3","doi-asserted-by":"publisher","DOI":"10.1002\/VIW.20250068","article-title":"Exploring exosome profiling via CytoFLEX\nNano flow cytometer: Approaches and applications","volume":"6","author":"Cao","year":"2025","journal-title":"View"},{"key":"2026072808065908100_cit4","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2022.114046","article-title":"Metabolites\nas extracellular vesicle cargo in health, cancer, pleural effusion,\nand cardiovascular diseases: An emerging field of study to diagnostic\nand therapeutic purposes","volume":"157","author":"Zhang","year":"2023","journal-title":"Biomed. Pharmacother."},{"issue":"5","key":"2026072808065908100_cit5","doi-asserted-by":"publisher","first-page":"1231","DOI":"10.1016\/j.ymthe.2023.02.013","article-title":"Exploiting\nthe biogenesis of extracellular vesicles for bioengineering and therapeutic\ncargo loading","volume":"31","author":"Ra\u0308dler","year":"2023","journal-title":"Mol. Ther."},{"issue":"3","key":"2026072808065908100_cit6","doi-asserted-by":"publisher","DOI":"10.1002\/VIW.20240121","article-title":"Glycopattern\ncomparison of sperm and exosomes from conventional in\nvitro fertilization and rescue intracytoplasmic sperm injection: Enhancing\nsperm motility through exosome-mediated glycan modulation","volume":"6","author":"Ramzan","year":"2025","journal-title":"View"},{"issue":"10","key":"2026072808065908100_cit7","doi-asserted-by":"publisher","first-page":"8672","DOI":"10.1021\/jacs.4c18110","article-title":"Efficient Metabolomics Profiling\nfrom Plasma Extracellular Vesicles Enables Accurate Diagnosis of Early\nGastric Cancer","volume":"147","author":"Bu","year":"2025","journal-title":"J. Am. Chem. Soc."},{"issue":"4","key":"2026072808065908100_cit8","doi-asserted-by":"publisher","first-page":"1203","DOI":"10.1007\/s10555-021-10014-2","article-title":"The role of the metabolite cargo\nof extracellular vesicles in tumor progression","volume":"40","author":"Harmati","year":"2021","journal-title":"Cancer Metastasis Rev."},{"issue":"6","key":"2026072808065908100_cit9","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1038\/s41580-019-0108-4","article-title":"Identification of bioactive\nmetabolites using activity metabolomics","volume":"20","author":"Rinschen","year":"2019","journal-title":"Nat.\nRev. Mol. Cell Biol."},{"issue":"1","key":"2026072808065908100_cit10","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1038\/s41392-023-01399-3","article-title":"Small molecule metabolites: discovery\nof biomarkers and therapeutic\ntargets","volume":"8","author":"Qiu","year":"2023","journal-title":"Signal Transduction Targeted Ther."},{"issue":"7","key":"2026072808065908100_cit11","doi-asserted-by":"publisher","DOI":"10.1002\/smll.202411871","article-title":"Metabolites\nin Serum Small Extracellular Vesicles Instead of Small Extracellular\nVesicles-depleted Serum Have Better Diagnostic Value for Cancers at\nEarly Stage","volume":"21","author":"Su","year":"2025","journal-title":"Small"},{"key":"2026072808065908100_cit12","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2025.105706","article-title":"Serum metabolic fingerprints encode functional biomarkers for ovarian\ncancer diagnosis: a large-scale cohort study","volume":"115","author":"Liu","year":"2025","journal-title":"eBioMedicine"},{"issue":"14","key":"2026072808065908100_cit13","doi-asserted-by":"publisher","first-page":"8314","DOI":"10.1021\/acs.analchem.8b01726","article-title":"High-Performance\nChemical\nIsotope Labeling Liquid Chromatography Mass Spectrometry for Exosome\nMetabolomics","volume":"90","author":"Luo","year":"2018","journal-title":"Anal. Chem."},{"issue":"16","key":"2026072808065908100_cit14","doi-asserted-by":"publisher","first-page":"3824","DOI":"10.7150\/thno.19890","article-title":"Metabolomic\nProfiling of Extracellular Vesicles and\nAlternative Normalization Methods Reveal Enriched Metabolites and\nStrategies to Study Prostate Cancer-Related Changes","volume":"7","author":"Puhka","year":"2017","journal-title":"Theranostics"},{"key":"2026072808065908100_cit15","doi-asserted-by":"publisher","DOI":"10.1016\/j.chroma.2021.461942","article-title":"Ultrafiltration\ncombing with phospholipid affinity-based isolation for metabolomic\nprofiling of urinary extracellular vesicles","volume":"1640","author":"Lou","year":"2021","journal-title":"J. Chromatogr. A"},{"issue":"5","key":"2026072808065908100_cit16","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1021\/acsmeasuresciau.2c00019","article-title":"MALDI-TOF Mass Spectrometry\nin Clinical\nAnalysis and Research","volume":"2","author":"Li","year":"2022","journal-title":"ACS Meas. Sci. Au"},{"issue":"45","key":"2026072808065908100_cit17","doi-asserted-by":"publisher","DOI":"10.1002\/adfm.201903609","article-title":"Silicon-Based Laser Desorption Ionization Mass Spectrometry\nfor the Analysis of Biomolecules: A Progress Report","volume":"29","author":"Iakab","year":"2019","journal-title":"Adv. Funct. Mater."},{"issue":"10","key":"2026072808065908100_cit18","doi-asserted-by":"publisher","DOI":"10.1002\/smtd.202100762","article-title":"Nanostructured Substrates\nas Matrices for Surface Assisted Laser Desorption\/Ionization Mass\nSpectrometry: A Progress Report from Material Research to Biomedical\nApplications","volume":"5","author":"Ma","year":"2021","journal-title":"Small Methods"},{"issue":"24","key":"2026072808065908100_cit19","doi-asserted-by":"publisher","first-page":"11747","DOI":"10.1021\/ac401662r","article-title":"LDI-MS Assisted\nby Chemical-Free\nGold Nanoparticles: Enhanced Sensitivity and Reduced Background in\nthe Low-Mass Region","volume":"85","author":"Amendola","year":"2013","journal-title":"Anal. Chem."},{"issue":"2","key":"2026072808065908100_cit20","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1021\/acscentsci.7b00546","article-title":"Metabolic\nFingerprinting on a Plasmonic Gold Chip for\nMass Spectrometry Based in Vitro Diagnostics","volume":"4","author":"Sun","year":"2018","journal-title":"ACS Central Sci."},{"key":"2026072808065908100_cit21","doi-asserted-by":"publisher","DOI":"10.1016\/j.trac.2025.118190","article-title":"Advances in nanomaterials\nbased laser desorption\/ionization mass spectrometry for metabolic\nanalysis","volume":"186","author":"Yang","year":"2025","journal-title":"Trends Anal. Chem."},{"issue":"4","key":"2026072808065908100_cit22","doi-asserted-by":"publisher","first-page":"1626","DOI":"10.1021\/ac061747w","article-title":"Gold Nanoparticles\nas Assisted Matrix for Determining\nNeutral Small Carbohydrates through Laser Desorption\/Ionization Time-of-Flight\nMass Spectrometry","volume":"79","author":"Su","year":"2007","journal-title":"Anal. Chem."},{"issue":"11","key":"2026072808065908100_cit23","doi-asserted-by":"publisher","first-page":"1931","DOI":"10.1007\/s13361-015-1223-x","article-title":"Inkjet-Printed\nGold Nanoparticle Surfaces for the Detection of Low Molecular Weight\nBiomolecules by Laser Desorption\/Ionization Mass Spectrometry","volume":"26","author":"Marsico","year":"2015","journal-title":"J. Am. Soc. Mass Spectrom."},{"issue":"4","key":"2026072808065908100_cit24","doi-asserted-by":"publisher","DOI":"10.1002\/smll.202409714","article-title":"Noble Metal Nanoparticle Assisted\nMass Spectrometry for Metabolite-Based In Vitro Diagnostics","volume":"21","author":"Liu","year":"2025","journal-title":"Small"},{"issue":"4","key":"2026072808065908100_cit25","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1039\/D4NA00393D","article-title":"Extracellular vesicles:\nfrom intracellular\ntrafficking molecules to fully fortified delivery vehicles for cancer\ntherapeutics","volume":"7","author":"Mohamed","year":"2025","journal-title":"Nanoscale Adv."},{"issue":"11","key":"2026072808065908100_cit26","doi-asserted-by":"publisher","first-page":"7024","DOI":"10.1021\/la200212c","article-title":"Phospholipid Membrane\nEncapsulation of Nanoparticles for Surface-Enhanced Raman Scattering","volume":"27","author":"Ip","year":"2011","journal-title":"Langmuir"},{"issue":"19","key":"2026072808065908100_cit27","doi-asserted-by":"publisher","first-page":"7743","DOI":"10.1021\/acs.analchem.3c00929","article-title":"Encoded Fusion-Mediated\nMicroRNA Signature Profiling of Tumor-Derived\nExtracellular Vesicles for Pancreatic Cancer Diagnosis","volume":"95","author":"Feng","year":"2023","journal-title":"Anal. Chem."},{"issue":"2","key":"2026072808065908100_cit28","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1021\/acssensors.2c01683","article-title":"Highly Effective\nDetection\nof Exosomal miRNAs in Plasma Using Liposome-Mediated Transfection\nCRISPR\/Cas13a","volume":"8","author":"Zhang","year":"2023","journal-title":"ACS Sens."},{"issue":"6","key":"2026072808065908100_cit29","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1586\/14737159.2015.1039515","article-title":"Choline\nmetabolism-based molecular diagnosis of cancer: an update","volume":"15","author":"Glunde","year":"2015","journal-title":"Expert Rev. Mol. Diagn."},{"key":"2026072808065908100_cit30","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1234887","article-title":"Choline metabolism\nand its implications in cancer","volume":"13","author":"Yao","year":"2023","journal-title":"Front. Oncol."},{"issue":"2","key":"2026072808065908100_cit31","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1203\/00006450-198802000-00001","article-title":"Hypoxanthine\nas an Indicator of Hypoxia: Its Role in Health and Disease through\nFree Radical Production","volume":"23","author":"Saugstad","year":"1988","journal-title":"Pediatr. Res."},{"issue":"1","key":"2026072808065908100_cit32","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-50866-y","article-title":"(1)H-NMR metabolomics analysis identifies hypoxanthine\nas a novel metastasis-associated metabolite in breast cancer","volume":"14","author":"Shakartalla","year":"2024","journal-title":"Sci. Rep."},{"issue":"1","key":"2026072808065908100_cit33","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1038\/s41589-024-01689-z","article-title":"Phospholipid biosynthesis\nmodulates nucleotide metabolism and reductive capacity","volume":"21","author":"Zhu","year":"2025","journal-title":"Nat. Chem. Biol."},{"issue":"5","key":"2026072808065908100_cit34","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1038\/s41568-023-00557-7","article-title":"Nucleotide metabolism:\na pan-cancer metabolic dependency","volume":"23","author":"Mullen","year":"2023","journal-title":"Nat. Rev.\nCancer"},{"issue":"1","key":"2026072808065908100_cit35","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-025-02141-x","article-title":"Energy\nmetabolism in health and diseases","volume":"10","author":"Liu","year":"2025","journal-title":"Signal Transduction\nTargeted Ther."},{"issue":"5","key":"2026072808065908100_cit36","doi-asserted-by":"publisher","first-page":"1056","DOI":"10.3390\/cells10051056","article-title":"Mechanisms of Metabolic Reprogramming in Cancer Cells\nSupporting Enhanced Growth and Proliferation","volume":"10","author":"Schiliro","year":"2021","journal-title":"Cells"},{"issue":"8","key":"2026072808065908100_cit37","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-024-06930-0","article-title":"Emerging mechanisms\nand promising approaches in pancreatic cancer metabolism","volume":"15","author":"Wu","year":"2024","journal-title":"Cell Death Dis."},{"issue":"34","key":"2026072808065908100_cit38","doi-asserted-by":"publisher","first-page":"11821","DOI":"10.1021\/acs.analchem.2c02072","article-title":"Metabolic-Dysregulation-Based\niEESI-MS Reveals Potential Biomarkers\nAssociated with Early-Stage and Progressive Colorectal Cancer","volume":"94","author":"Zheng","year":"2022","journal-title":"Anal. Chem."},{"issue":"8","key":"2026072808065908100_cit39","doi-asserted-by":"publisher","first-page":"457","DOI":"10.3390\/metabo14080457","article-title":"Alterations\nin Choline Metabolism in Non-Obese Individuals with Insulin Resistance\nand Type 2 Diabetes Mellitus","volume":"14","author":"Al-Sulaiti","year":"2024","journal-title":"Metabolites"}],"container-title":["Analytical Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.analchem.6c04341","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/ancham\/article-pdf\/98\/29\/21935\/65970053\/acs.analchem.6c04341.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/ancham\/article-pdf\/98\/29\/21935\/65970053\/acs.analchem.6c04341.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T12:21:39Z","timestamp":1785241299000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/ancham\/article\/98\/29\/21935\/5211537\/Membrane-Fusion-Assisted-Laser-Desorption"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,16]]},"references-count":39,"journal-issue":{"issue":"29","published-online":{"date-parts":[[2026,7,16]]},"published-print":{"date-parts":[[2026,7,28]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.analchem.6c04341","relation":{},"ISSN":["0003-2700","1520-6882"],"issn-type":[{"value":"0003-2700","type":"print"},{"value":"1520-6882","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,16]]}}}