{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T11:18:53Z","timestamp":1788434333076,"version":"build-2803163510"},"reference-count":40,"publisher":"American Chemical Society (ACS)","issue":"34","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100004334","name":"Merck","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100004334","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Accelerating the discovery and development of life-saving therapeutics and vaccines requires a commensurate level of analytical innovations, especially high-throughput (HT) methodologies for simultaneous multicomponent analyses traditionally used in fast-paced laboratory settings. HT screening is a critical step to enable lead candidate design, selection, and formulation at aggressive timelines. Current methods used for this purpose, such as liquid chromatography-mass spectrometry (LC-MS)-based approaches, are intrinsically low-throughput. Such assays are less meaningful in settings where processing thousands of samples is required to guide critical decisions quickly. Acoustic droplet ejection-open-port interface-mass spectrometry (ADE-OPI-MS) is a cutting-edge technology that eliminates the need for LC by introducing nanoliter-scale samples to an MS via acoustic ejection at speeds of &amp;lt;1 s per sample while minimizing matrix effects and data variability compared to more established HT sample introduction methods. Previously, ADE-OPI-MS has been demonstrated for purified protein standards in simple matrices, but its use on proteins within complex matrices remains underexplored. Biopharmaceutical samples often contain salts, buffers, and other components that make sample detection challenging without some form of sample cleanup. Herein, an integrated workflow combining sample preparation, detection, and quantification for ADE-OPI-MS is introduced, streamlining relative quantification of products spiked into complex matrices. Using this analytical framework, effective quantification of myoglobin, virus-like particle L1 protein, and monoclonal antibodies in complex cell lysate and drug process matrices is straightforward while also minimizing manual labor with automatable sample preparation capable of analyzing a full 384-well plate in under 12.5 min.<\/jats:p>","DOI":"10.1021\/acs.analchem.6c03005","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T18:01:28Z","timestamp":1787248888000},"page":"25146-25154","source":"Crossref","is-referenced-by-count":0,"title":["Acoustic Droplet\nEjection High-Resolution Mass Spectrometry\nEnables High-Throughput Analysis of Proteins in Complex Biologic and\nVaccine Matrices"],"prefix":"10.1021","volume":"98","author":[{"given":"Jarrod","family":"Laro","sequence":"first","affiliation":[{"name":"University of Oklahoma , , , ,","place":["Norman, Oklahoma, United States, 73019"]},{"name":"San Diego State University , , , ,","place":["San Diego, California, United States, 92182"]},{"name":"MRL Merck & Co., Inc. , , , ,","place":["Rahway, New Jersey, United States, 07065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6006-5047","authenticated-orcid":true,"given":"Rodell C.","family":"Barrientos","sequence":"additional","affiliation":[{"name":"MRL Merck & Co., Inc. , , , ,","place":["Rahway, New Jersey, United States, 07065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eli","family":"Larson","sequence":"additional","affiliation":[{"name":"MRL Merck & Co., Inc. , , , ,","place":["Rahway, New Jersey, United States, 07065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7352-6391","authenticated-orcid":true,"given":"Erik","family":"Regalado","sequence":"additional","affiliation":[{"name":"MRL Merck & Co., Inc. , , , ,","place":["Rahway, New Jersey, United States, 07065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Appiah-Amponsah","sequence":"additional","affiliation":[{"name":"MRL Merck & Co., Inc. , , , ,","place":["Rahway, New Jersey, United States, 07065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0508-4357","authenticated-orcid":true,"given":"Chang","family":"Liu","sequence":"additional","affiliation":[{"name":"SCIEX , , ,","place":["Concord, Ontario, Canada, L4K 4 V8"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Gouker","sequence":"additional","affiliation":[{"name":"MRL Merck & Co., Inc. , , , ,","place":["Rahway, New Jersey, United States, 07065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2991-6760","authenticated-orcid":true,"given":"Devin M.","family":"Makey","sequence":"additional","affiliation":[{"name":"MRL Merck & Co., Inc. , , , ,","place":["Rahway, New Jersey, United States, 07065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8590-9787","authenticated-orcid":true,"given":"Hang","family":"Hu","sequence":"additional","affiliation":[{"name":"MRL Merck & Co., Inc. , , , ,","place":["Rahway, New Jersey, United States, 07065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7846-257X","authenticated-orcid":true,"given":"Ophelia","family":"Ukaegbu","sequence":"additional","affiliation":[{"name":"MRL Merck & Co., Inc. , , , ,","place":["Rahway, New Jersey, United States, 07065"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"2026090306465286300_cit1","doi-asserted-by":"publisher","DOI":"10.1186\/s12951-021-00806-7","article-title":"Virus-like Particles: Preparation,\nImmunogenicity and Their Roles as Nanovaccines and Drug Nanocarriers","volume":"19","author":"Nooraei","year":"2021","journal-title":"J. Nanobiotechnol."},{"issue":"23","key":"2026090306465286300_cit2","doi-asserted-by":"publisher","first-page":"5951","DOI":"10.1007\/s00216-019-01998-6","article-title":"Virus-like\nParticle Size and Molecular Weight\/Mass Determination Applying Gas-Phase\nElectrophoresis (Native nES GEMMA)","volume":"411","author":"Weiss","year":"2019","journal-title":"Anal. Bioanal.\nChem."},{"issue":"9","key":"2026090306465286300_cit3","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1038\/s41423-022-00897-8","article-title":"Virus-like Particle Vaccinology,\nfrom Bench to Bedside","volume":"19","author":"Mohsen","year":"2022","journal-title":"Cell. Mol. Immunol."},{"issue":"1","key":"2026090306465286300_cit4","doi-asserted-by":"publisher","DOI":"10.5812\/ijpr-127042","article-title":"A Review of Virus-Like Particle-Based\nSARS-CoV-2 Vaccines in Clinical Trial Phases","volume":"21","author":"Sharifzadeh","year":"2022","journal-title":"Iran. J. Pharm. Res."},{"issue":"3","key":"2026090306465286300_cit5","doi-asserted-by":"publisher","DOI":"10.3390\/antib9030034","article-title":"Monoclonal Antibodies\nin Cancer Therapy","volume":"9","author":"Zahavi","year":"2020","journal-title":"Antibodies"},{"issue":"8","key":"2026090306465286300_cit6","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1038\/s41573-023-00709-2","article-title":"Antibody\u2013Drug\nConjugates Come of Age in Oncology","volume":"22","author":"Dumontet","year":"2023","journal-title":"Nat. Rev.\nDrug Discovery"},{"issue":"1","key":"2026090306465286300_cit7","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1111\/all.15091","article-title":"Development\nand Preclinical Evaluation of Virus-like\nParticle Vaccine against COVID-19 Infection","volume":"77","author":"Yilmaz","year":"2022","journal-title":"Allergy"},{"issue":"22","key":"2026090306465286300_cit8","doi-asserted-by":"publisher","first-page":"5487","DOI":"10.1039\/C8AN01178H","article-title":"J. Qualitative Analysis of Antibody\u2013Drug Conjugates\n(ADCs): An Experimental Comparison of Analytical Techniques of Cysteine-Linked\nADCs","volume":"143","author":"Ka\u0308llsten","year":"2018","journal-title":"Analyst"},{"key":"2026090306465286300_cit9","doi-asserted-by":"publisher","first-page":"960","DOI":"10.1080\/19420862.2018.1494487","article-title":"Characterization\nof in Vivo Biotransformations for Trastuzumab Emtansine by High-Resolution\nAccurate-Mass Mass Spectrometry","volume":"10","author":"He","year":"2018","journal-title":"mAbs"},{"key":"2026090306465286300_cit10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jchromb.2018.07.039","article-title":"Characterizing Various Monoclonal Antibodies with Milder\nReversed Phase Chromatography Conditions","volume":"1096","author":"Boba\u0301ly","year":"2018","journal-title":"J.\nChromatogr. B"},{"issue":"1","key":"2026090306465286300_cit11","doi-asserted-by":"publisher","DOI":"10.1186\/s13321-020-00424-9","article-title":"Review on Natural Products Databases:\nWhere to Find\nData in 2020","volume":"12","author":"Sorokina","year":"2020","journal-title":"J. Cheminf."},{"issue":"6424","key":"2026090306465286300_cit12","doi-asserted-by":"publisher","DOI":"10.1126\/science.aat0805","article-title":"The Importance\nof Synthetic Chemistry in the Pharmaceutical Industry","volume":"363","author":"Campos","year":"2019","journal-title":"Science"},{"issue":"3","key":"2026090306465286300_cit13","doi-asserted-by":"publisher","DOI":"10.1128\/msystems.00844-24","article-title":"Rationally Minimizing\nNatural Product Libraries Using Mass Spectrometry","volume":"10","author":"Ness","year":"2025","journal-title":"mSystems"},{"issue":"6","key":"2026090306465286300_cit14","doi-asserted-by":"publisher","first-page":"712","DOI":"10.1038\/s41589-022-01234-w","article-title":"Modeling the Expansion of Virtual\nScreening Libraries","volume":"19","author":"Lyu","year":"2023","journal-title":"Nat. Chem. Biol."},{"issue":"3","key":"2026090306465286300_cit15","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1038\/s41573-020-00114-z","article-title":"Natural\nProducts in Drug Discovery: Advances and Opportunities","volume":"20","author":"Atanasov","year":"2021","journal-title":"Nat. Rev. Drug Discovery"},{"issue":"39","key":"2026090306465286300_cit16","doi-asserted-by":"publisher","first-page":"13566","DOI":"10.1021\/acs.analchem.2c03211","article-title":"High-Throughput\nIntact Protein Analysis for Drug Discovery Using Infrared Matrix-Assisted\nLaser Desorption Electrospray Ionization Mass Spectrometry","volume":"94","author":"Pu","year":"2022","journal-title":"Anal. Chem."},{"issue":"2","key":"2026090306465286300_cit17","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1002\/mas.21515","article-title":"The Quest for Improved Reproducibility\nin MALDI Mass Spectrometry","volume":"37","author":"O\u2019Rourke","year":"2018","journal-title":"Mass Spectrom. Rev."},{"issue":"1","key":"2026090306465286300_cit18","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202114850","article-title":"Advances in High-throughput Mass Spectrometry in Drug Discovery","volume":"15","author":"Duen\u0303as","year":"2023","journal-title":"EMBO Mol. Med."},{"issue":"10","key":"2026090306465286300_cit19","doi-asserted-by":"publisher","first-page":"4619","DOI":"10.1021\/acs.analchem.0c05277","article-title":"Native Mass Spectrometry\nImaging of Proteins and Protein\nComplexes by Nano-DESI","volume":"93","author":"Hale","year":"2021","journal-title":"Anal. Chem."},{"issue":"17","key":"2026090306465286300_cit20","doi-asserted-by":"publisher","first-page":"6468","DOI":"10.1021\/ac201390w","article-title":"Direct Ionization\nof Large Proteins and Protein Complexes by Desorption Electrospray\nIonization-Mass Spectrometry","volume":"83","author":"Ferguson","year":"2011","journal-title":"Anal. Chem."},{"issue":"14","key":"2026090306465286300_cit21","doi-asserted-by":"publisher","first-page":"5608","DOI":"10.1021\/acs.analchem.1c05353","article-title":"Native Ambient Mass\nSpectrometry Enables Analysis of Intact Endogenous Protein Assemblies\nup to 145 kDa Directly from Tissue","volume":"94","author":"Hale","year":"2022","journal-title":"Anal. Chem."},{"issue":"6","key":"2026090306465286300_cit22","doi-asserted-by":"publisher","first-page":"3256","DOI":"10.1021\/acs.analchem.6b04889","article-title":"RapidFire Mass Spectrometry with\nEnhanced Throughput as an Alternative to Liquid\u2013Liquid Salt\nAssisted Extraction and LC\/MS Analysis for Sulfonamides in Honey","volume":"89","author":"Veach","year":"2017","journal-title":"Anal. Chem."},{"issue":"3","key":"2026090306465286300_cit23","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1097\/FTD.0000000000000139","article-title":"Performance of the New RapidFire\nSystem for Therapeutic Monitoring of Immunosuppressants","volume":"37","author":"Grote-Koska","year":"2015","journal-title":"Ther. Drug Monit."},{"issue":"45","key":"2026090306465286300_cit24","doi-asserted-by":"publisher","first-page":"16717","DOI":"10.1021\/acs.analchem.3c03788","article-title":"Development of an\nAutomated, High-Throughput Methodology\nfor Native Mass Spectrometry and Collision-Induced Unfolding","volume":"95","author":"Juliano","year":"2023","journal-title":"Anal. Chem."},{"issue":"6","key":"2026090306465286300_cit25","doi-asserted-by":"publisher","first-page":"978","DOI":"10.1101\/gr.247353.118","article-title":"One Minute\nAnalysis of 200 Histone\nPosttranslational Modifications by Direct Injection Mass Spectrometry","volume":"29","author":"Sidoli","year":"2019","journal-title":"Genome Res."},{"issue":"18","key":"2026090306465286300_cit26","doi-asserted-by":"publisher","first-page":"12242","DOI":"10.1021\/acs.analchem.0c01632","article-title":"Ultrahigh-Throughput\nESI-MS: Sampling Pushed to Six Samples per Second by Acoustic Ejection\nMass Spectrometry","volume":"92","author":"Ha\u0308be","year":"2020","journal-title":"Anal. Chem."},{"issue":"31","key":"2026090306465286300_cit27","doi-asserted-by":"publisher","first-page":"10850","DOI":"10.1021\/acs.analchem.1c01137","article-title":"Acoustic Ejection Mass Spectrometry for High-Throughput\nAnalysis","volume":"93","author":"Zhang","year":"2021","journal-title":"Anal. Chem."},{"issue":"1","key":"2026090306465286300_cit28","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-48563-z","article-title":"Acoustic\nEjection Mass Spectrometry Empowers Ultra-Fast Protein Biomarker Quantification","volume":"15","author":"Van Puyvelde","year":"2024","journal-title":"Nat. Commun."},{"issue":"11","key":"2026090306465286300_cit29","doi-asserted-by":"publisher","first-page":"3285","DOI":"10.1016\/j.xphs.2020.07.025","article-title":"Acoustic Droplet Ejection and Open\nPort Interface for\nRapid Analysis of Metabolic Stability Assays","volume":"109","author":"Hollenbeck","year":"2020","journal-title":"J. Pharm. Sci."},{"key":"2026090306465286300_cit30","doi-asserted-by":"publisher","first-page":"13525","DOI":"10.1021\/acs.analchem.0c03006","article-title":"Ultrahigh-Throughput\nand Chromatography-Free\nBioanalysis of Polar Analytes with Acoustic Ejection Mass Spectrometry","volume":"92","author":"Wagner","year":"2020","journal-title":"Anal. Chem."},{"issue":"29","key":"2026090306465286300_cit31","doi-asserted-by":"publisher","first-page":"12040","DOI":"10.1021\/acs.analchem.4c02110","article-title":"High-Throughput Screening for Oligonucleotide\nDetection\nby ADE-OPI-MS","volume":"96","author":"Hu","year":"2024","journal-title":"Anal. Chem."},{"issue":"15","key":"2026090306465286300_cit32","doi-asserted-by":"publisher","first-page":"6071","DOI":"10.1021\/acs.analchem.0c04312","article-title":"Direct\nAnalysis from Phase-Separated\nLiquid Samples Using ADE-OPI-MS: Applicability to High-Throughput\nScreening for Inhibitors of Diacylglycerol Acyltransferase 2","volume":"93","author":"Wen","year":"2021","journal-title":"Anal. Chem."},{"issue":"3","key":"2026090306465286300_cit33","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1016\/j.jpba.2007.11.002","article-title":"Quantitative Aspects\nof the Analysis of the Monoclonal Antibody Trastuzumab Using High-Performance\nLiquid Chromatography Coupled with Electrospray Mass Spectrometry","volume":"46","author":"Damen","year":"2008","journal-title":"J. Pharm. Biomed. Anal."},{"issue":"1","key":"2026090306465286300_cit34","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1007\/s40495-017-0118-x","article-title":"LC\u2013MS Challenges\nin Characterizing and Quantifying Monoclonal Antibodies (mAb) and\nAntibody-Drug Conjugates (ADC) in Biological Samples","volume":"4","author":"Wei","year":"2018","journal-title":"Curr. Pharmacol. Rep."},{"issue":"12","key":"2026090306465286300_cit35","doi-asserted-by":"publisher","first-page":"2569","DOI":"10.1007\/s00216-019-01699-0","article-title":"Application of Triple Quadrupole\nMass Spectrometry for the Characterization of Antibody\u2013Drug\nConjugates","volume":"411","author":"Ka\u0308llsten","year":"2019","journal-title":"Anal. Bioanal. Chem."},{"issue":"1","key":"2026090306465286300_cit36","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1021\/jasms.2c00276","article-title":"Ultrahigh-Throughput Intact Protein Analysis with Acoustic\nEjection Mass Spectrometry","volume":"34","author":"Zacharias","year":"2023","journal-title":"J. Am. Soc. Mass\nSpectrom."},{"issue":"11","key":"2026090306465286300_cit37","first-page":"1000","article-title":"Buffer Considerations for LC and\nLC\u2013MS","volume":"27","author":"Subirats","year":"2009","journal-title":"LCGC North Am."},{"issue":"1","key":"2026090306465286300_cit38","doi-asserted-by":"publisher","DOI":"10.5702\/massspectrometry.A0031","article-title":"Salt Tolerance\nEnhancement of Liquid Chromatography-Matrix-Assisted Laser Desorption\/Ionization-Mass\nSpectrometry Using Matrix Additive Methylenediphosphonic Acid","volume":"3","author":"Ohta","year":"2014","journal-title":"Mass Spectrom."},{"key":"2026090306465286300_cit39","doi-asserted-by":"publisher","DOI":"10.1016\/j.chroma.2025.465851","article-title":"Two-Dimensional Size Exclusion Reversed-Phase\nLiquid Chromatography for Quantitative Analysis of L1 Proteins in\nComplex Vaccine Matrices","volume":"1748","author":"Arcinas","year":"2025","journal-title":"J. Chromatogr. A"},{"issue":"22","key":"2026090306465286300_cit40","doi-asserted-by":"publisher","first-page":"3932","DOI":"10.1091\/mbc.E15-07-0512","article-title":"Quantitative\nNature of Overexpression Experiments","volume":"26","author":"Moriya","year":"2015","journal-title":"Mol. Biol.\nCell"}],"container-title":["Analytical Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.analchem.6c03005","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/ancham\/article-pdf\/98\/34\/25146\/66913337\/acs.analchem.6c03005.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/ancham\/article-pdf\/98\/34\/25146\/66913337\/acs.analchem.6c03005.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T10:46:58Z","timestamp":1788432418000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/ancham\/article\/98\/34\/25146\/5278514\/Acoustic-Droplet-Ejection-High-Resolution-Mass"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,20]]},"references-count":40,"journal-issue":{"issue":"34","published-online":{"date-parts":[[2026,8,20]]},"published-print":{"date-parts":[[2026,9,1]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.analchem.6c03005","relation":{"has-preprint":[{"id-type":"doi","id":"10.26434\/chemrxiv-2025-0rz39","asserted-by":"object"}]},"ISSN":["0003-2700","1520-6882"],"issn-type":[{"value":"0003-2700","type":"print"},{"value":"1520-6882","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,20]]}}}