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However, conventional mass spectrometry (MS) methods exhibit limited sensitivity for the direct detection of protein biomarkers. In this study, we developed an immuno\u2010 mesoporous silica nanoparticle \u2010mass tags (immuno\u2010MSN\u2010MTs) technology based on mass spectrometry signal amplification for the detection of AD biomarkers in blood and brain tissues. When coupled with paper spray ionization mass spectrometry (PSI MS), this method enables highly sensitive quantitative analysis of AD biomarkers in plasma at the picogram per milliliter (pg\/mL) level. Normalization of the mass tag signals using internal standards allows for the quantitative determination of protein biomarkers in AD mice across different months. Furthermore, the combination of immuno\u2010MSN\u2010MT with desorption electrospray ionization (DESI) imaging enables the simultaneous detection of protein biomarkers and small\u2010molecule metabolites. This not only facilitates the localized detection of protein biomarkers in the brain tissues of AD mice but also enables the investigation of metabolite differences in lesion areas. These findings provide a theoretical basis for the early diagnosis of AD and the elucidation of the micro\u2010mechanisms underlying A\u03b2 aggregation, while offering a multi\u2010scale perspective for AD pathological research.<\/jats:p>","DOI":"10.1002\/smll.202511311","type":"journal-article","created":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T12:08:18Z","timestamp":1766405298000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immuno\u2010MSN\u2010MTs Based Multiplex Biomarker Analysis: A Multimodal Mass Spectrometry Approach for Alzheimer's Disease Detection in Diverse Biospecimens"],"prefix":"10.1002","volume":"22","author":[{"given":"Tong","family":"Pei","sequence":"first","affiliation":[{"name":"State Key Laboratory of Materials Low\u2010Carbon Recycling Center of Excellence for Environmental Safety and Biological Effects Department of Chemistry College of Chemistry and Life Science Beijing University of Technology  Beijing P. 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