{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T11:42:19Z","timestamp":1792496539219,"version":"4.5.0"},"reference-count":43,"publisher":"American Chemical Society (ACS)","issue":"41","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100000165","name":"Division of Chemistry","doi-asserted-by":"publisher","award":["2506157"],"award-info":[{"award-number":["2506157"]}],"id":[{"id":"10.13039\/100000165","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["5R01GM139338"],"award-info":[{"award-number":["5R01GM139338"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The clinical success of messenger ribonucleic acid (mRNA) therapeutics has driven the need for robust analytical techniques capable of characterizing mixtures of megadalton (MDa) constructs. A critical attribute of these therapeutics is the presence and length of the 3\u2032 poly(A) tail, which governs mRNA stability and translational efficiency. Charge detection mass spectrometry (CDMS) was used to distinguish and quantify intact MDa mRNA variants differing only by the poly(A) content. Initial analysis under native-like conditions was limited by salt adduction, but a 75% methanol solution resulted in nearly a five-fold increase in charge (from \u223c60e to \u223c280e) and substantially less adduction. Measured masses of the intact mRNA were 1.054 MDa and 1.027 MDa for the tailed and non-tailed mRNA constructs, respectively, consistent with the theoretical 26.6 kDa mass difference. Mixtures of various compositions resulted in broad, unresolved peaks at intermediate mass owing to residual salt adduction. A constrained Gaussian deconvolution of these data enabled accurate quantification across seven different mole fractions (R2 = 0.978). Notably, an analysis of a subpopulation of the highest charge-state ions revealed separation into two distinct peaks, demonstrating that mass resolution for MDa mRNA analysis is limited by adduction rather than instrumental factors, motivating additional studies on methods to increase charging for more accurate quantification. These results establish CDMS as a powerful, top-down method for precise monitoring of mRNA heterogeneity and degradation in high molecular weight therapeutics.<\/jats:p>","DOI":"10.1021\/acs.analchem.6c03007","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T21:01:39Z","timestamp":1791320499000},"page":"29507-29514","source":"Crossref","is-referenced-by-count":0,"title":["Quantification\nof Intact MDa Poly(A)-Tailed and Non-Tailed\nmRNA Fractions with Charge Detection Mass Spectrometry"],"prefix":"10.1021","volume":"98","author":[{"given":"Julian","family":"Robles","sequence":"first","affiliation":[{"name":"University of California , , , ,","place":["Berkeley, California, United States, 94720-1460"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary M.","family":"Miller","sequence":"additional","affiliation":[{"name":"University of California , , , ,","place":["Berkeley, California, United States, 94720-1460"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron M.","family":"Roe","sequence":"additional","affiliation":[{"name":"Scribe Therapeutics , , ,","place":["Alameda, California, United States, 94501"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie M.","family":"Thibert","sequence":"additional","affiliation":[{"name":"Scribe Therapeutics , , ,","place":["Alameda, California, United States, 94501"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew R.","family":"Gardner","sequence":"additional","affiliation":[{"name":"Scribe Therapeutics , , ,","place":["Alameda, California, United States, 94501"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janelle Tricia M.","family":"Magaling","sequence":"additional","affiliation":[{"name":"Scribe Therapeutics , , ,","place":["Alameda, California, United States, 94501"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin W.","family":"Torpey","sequence":"additional","affiliation":[{"name":"Scribe Therapeutics , , ,","place":["Alameda, California, United States, 94501"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelica F.","family":"Castan\u0303eda","sequence":"additional","affiliation":[{"name":"Scribe Therapeutics , , ,","place":["Alameda, California, United States, 94501"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1733-3018","authenticated-orcid":true,"given":"Evan R.","family":"Williams","sequence":"additional","affiliation":[{"name":"University of California , , , ,","place":["Berkeley, California, United States, 94720-1460"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"issue":"4","key":"2026102006561203600_cit1","doi-asserted-by":"publisher","first-page":"102721","DOI":"10.1016\/j.omtn.2025.102721","article-title":"mRNA therapeutics: Transforming medicine through innovation\nin design, delivery, and disease treatment","volume":"36","author":"Ige","year":"2025","journal-title":"Molecular Therapy. 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Chem."},{"issue":"7","key":"2026102006561203600_cit4","doi-asserted-by":"publisher","first-page":"1629","DOI":"10.3390\/molecules30071629","article-title":"Current Analytical\nStrategies for mRNA-Based Therapeutics","volume":"30","author":"Camperi","year":"2025","journal-title":"Molecules"},{"key":"2026102006561203600_cit5","unstructured":"Analytical Procedures For Quality Of mRNA Vaccines\nAnd Therapeutics\n(Draft Guidelines\n          3rd Edition); United States Pharmacopeia, 2024. https:\/\/www.uspnf.com\/notices\/analytical-procedures-mrna-vaccines-20240802."},{"key":"2026102006561203600_cit6","doi-asserted-by":"publisher","first-page":"113105","DOI":"10.1016\/j.jpba.2020.113105","article-title":"Characterization\nof therapeutic oligonucleotides\nby liquid chromatography","volume":"182","author":"Goyon","year":"2020","journal-title":"J. Pharm. 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Mass\nSpectrom."},{"issue":"4","key":"2026102006561203600_cit30","doi-asserted-by":"publisher","first-page":"2776","DOI":"10.1021\/acs.analchem.8b04519","article-title":"Measurement of Individual Ions Sharply\nIncreases the\nResolution of Orbitrap Mass Spectra of Proteins","volume":"91","author":"Kafader","year":"2019","journal-title":"Anal. Chem."},{"issue":"20","key":"2026102006561203600_cit31","doi-asserted-by":"publisher","first-page":"10844","DOI":"10.1021\/jp510081v","article-title":"Charge Detection Mass\nSpectrometry for the Characterization\nof Mass and Surface Area of Composite Nanoparticles","volume":"119","author":"Doussineau","year":"2015","journal-title":"J. Phys. Chem. 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Mass Spectrom."},{"issue":"33","key":"2026102006561203600_cit41","doi-asserted-by":"publisher","first-page":"23297","DOI":"10.1021\/jacs.4c05885","article-title":"Charge Detection\nMass Spectrometry Reveals Conformational\nHeterogeneity in Megadalton-Sized Monoclonal Antibody Aggregates","volume":"146","author":"Jordan","year":"2024","journal-title":"J. Am. Chem. Soc."},{"key":"2026102006561203600_cit42","doi-asserted-by":"publisher","first-page":"17806","DOI":"10.1021\/acsnano.4c03503","article-title":"Characterization\nof Mass, Diameter, Density, and Surface Properties of Colloidal Nanoparticles\nEnabled by Charge Detection Mass Spectrometry","volume":"18","author":"Harper","year":"2024","journal-title":"ACS Nano"},{"issue":"33","key":"2026102006561203600_cit43","doi-asserted-by":"publisher","first-page":"11703","DOI":"10.1021\/acs.analchem.2c02572","article-title":"Effects\nof Molecular Size on Resolution\nin Charge Detection Mass Spectrometry","volume":"94","author":"Harper","year":"2022","journal-title":"Anal.\nChem."}],"container-title":["Analytical Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.analchem.6c03007","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/ancham\/article-pdf\/98\/41\/29507\/68764322\/acs.analchem.6c03007.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/ancham\/article-pdf\/98\/41\/29507\/68764322\/acs.analchem.6c03007.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T11:09:19Z","timestamp":1792494559000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/ancham\/article\/98\/41\/29507\/5445662\/Quantification-of-Intact-MDa-Poly-A-Tailed-and-Non"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,6]]},"references-count":43,"journal-issue":{"issue":"41","published-online":{"date-parts":[[2026,10,6]]},"published-print":{"date-parts":[[2026,10,20]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.analchem.6c03007","relation":{},"ISSN":["0003-2700","1520-6882"],"issn-type":[{"value":"0003-2700","type":"print"},{"value":"1520-6882","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,6]]}}}