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The rapid emergence of antibiotic resistance severely compromises treatment efficacy. However current conventional approaches fail to capture early molecular events preceding detectable resistance. Here, we used a gradient intermittent antibiotic exposure model to simulate stepwise resistance evolution and longitudinally acquired single\u2010cell Raman spectra across adaptive cycles. By integrating two\u2010dimensional correlation Raman spectroscopy (2D\u2010COS), we resolved the temporal sequence of molecular alterations during the phenotypic silent window. The earliest responses involved adjustments of pre\u2010existing biomass structures. Specifically, symmetric CH\n                    <jats:sub>2<\/jats:sub>\n                    and CH\n                    <jats:sub>3<\/jats:sub>\n                    vibrations changed first, reflecting membrane lipid and protein conformational shifts, followed by carbohydrate backbone and alkyl vibrations indicating initial metabolic adjustments. During a structural reorganization phase, amide III shifted earlier than amide I, suggesting protein conformational adjustment precedes content increase, while lipid chain vibration emerged concurrently. Subsequently, nucleic acid base and pyrimidine ring vibrations increased, culminating in the C\u2010D band representing newly synthesized biomass accumulation. This sequential cascade reveals that structural adaptation occurs prior to metabolic activation. Our work provides a detailed molecular basis for resistance evolution within the silent window and highlights single\u2010cell Raman\u2010based metabolic profiling for early detection.\n                  <\/jats:p>","DOI":"10.1002\/smtd.71050","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T06:14:36Z","timestamp":1789712076000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["D\n                    <sub>2<\/sub>\n                    O\u2010Labeled Single\u2010Cell Raman Spectroscopy Reveals the Evolutionary Trajectory of\n                    <i>Helicobacter pylori<\/i>\n                    During the Phenotypic Silent Window"],"prefix":"10.1002","author":[{"given":"Jiayu","family":"Zeng","sequence":"first","affiliation":[{"name":"Molecular Science and Biomedicine Laboratory (MBL) State Key Laboratory of Chemo and Biosensing College of Chemistry and Chemical Engineering College of Environmental Science and Engineering of Hunan Province Hunan University  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan","family":"Sheng","sequence":"additional","affiliation":[{"name":"Molecular Science and Biomedicine Laboratory (MBL) State Key Laboratory of Chemo and Biosensing College of Chemistry and Chemical Engineering College of Environmental Science and Engineering of Hunan Province Hunan University  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9182-1952","authenticated-orcid":false,"given":"Ye","family":"Qiu","sequence":"additional","affiliation":[{"name":"Molecular Science and Biomedicine Laboratory (MBL) State Key Laboratory of Chemo and Biosensing College of Chemistry and Chemical Engineering College of Environmental Science and Engineering of Hunan Province Hunan University  Changsha 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Laboratory of Chemo and Biosensing College of Chemistry and Chemical Engineering College of Environmental Science and Engineering of Hunan Province Hunan University  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(18)30398\u20102"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(05)77256\u20101"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines13070725"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2012.1701"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.2174\/1871530323666230824161901"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics13060551"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rgmx.2018.10.005"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/00042737\u2010199911000\u201000027"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.15.1528"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1385\/0\u201089603\u2010402\u2010X:275"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.20892\/j.issn.2095\u20103941.2018.0055"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22048"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1631\/jzus.b2200068"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkaf172"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcla.24885"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365\u20102672.2012.05351.x"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ese.2022.100187"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010025\u201066996\u2010y"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1039\/D5AN00802F"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/1751\u20107915.13519"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.analchem.0c02443"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscentsci.3c01438"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1420406112"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010017\u201016898\u2010x"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00216\u2010021\u201003691\u2010z"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2118836119"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.analchem.1c00431"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202410919"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.1302843"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1360\/03yb0085"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1366\/000370203322259039"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2201473119"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43016\u2010024\u201001024\u20108"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.analchem.1c01076"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1128\/jb.186.22.7610\u20107617.2004"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202217412"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.103376"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2021.644615"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40643\u2010022\u201000493\u20108"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2017.03.002"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41576\u2010020\u201000307\u20107"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.71302"}],"container-title":["Small 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