{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T02:21:01Z","timestamp":1783390861590,"version":"3.54.6"},"reference-count":90,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T00:00:00Z","timestamp":1775865600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Tuberculosis\u2013diabetes mellitus (TB-DM) is increasingly recognized as a syndemic in which chronic metabolic dysregulation amplifies tuberculosis severity, delays treatment response, and increases relapse and mortality. However, conventional systemic correlates soluble cytokines and bulk whole-blood transcriptomic signatures often appear broadly similar between TB and TB-DM. This highlights a key gap: clinically meaningful immune dysfunction in TB-DM likely resides in specific lung and blood cell states that are poorly resolved by bulk assays. Small extracellular vesicles (EVs) in plasma and bronchoalveolar lavage (BAL) provide a tractable \u201cliquid biopsy\u201d layer because their RNA and protein cargo can integrate information from infected macrophages, neutrophils, and epithelial\/endothelial compartments, and may also include pathogen-derived components. Yet most EV studies remain bulk and cell-agnostic, and interpretation is constrained by heterogeneous vesicle mixtures, selective cargo packaging, and co-isolated non-vesicular contaminants, issues that are especially problematic for nucleic-acid claims without rigorous controls. In this targeted narrative review (2010\u20132026), we argue that single-cell and multimodal immune reference atlases, including scRNA-seq\/CITE-seq, provide a needed scaffold to link EV cargo patterns to specific immune cell states, pathways, and anatomic compartments in TB-DM, enabling prioritized candidates and testable hypotheses. We outline three complementary frameworks: reference-atlas anchoring to project EV cargo modules onto atlas-defined immune states; orthogonal triangulation combining computational inference with immunoaffinity enrichment, targeted validation, and functional assays; and cautious use of \u201cdroplet-era\u201d extracellular signals as hypothesis-generating priors for EV-producing states. Implemented in longitudinal, clinically annotated cohorts with standardized EV workflows, atlas-guided EV profiling could yield cell-of-origin\u2013resolved biomarkers of TB-DM immunopathology and treatment response, while prioritizing mechanistically plausible targets for host-directed intervention.<\/jats:p>","DOI":"10.3390\/ijms27083437","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T08:49:02Z","timestamp":1776070142000},"page":"3437","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Single-Cell Immune Atlases to Map Small Extracellular Vesicle Cargo in Tuberculosis\u2013Diabetes Comorbidity: A Narrative Review and Conceptual Roadmap"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-6335-1627","authenticated-orcid":false,"given":"Ramona","family":"Cioboata","sequence":"first","affiliation":[{"name":"Department of Pneumology, University of Medicine and Pharmacy, 200349 Craiova, Romania"},{"name":"Department of Pneumology, Victor Babes University Hospital, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3856-7917","authenticated-orcid":false,"given":"Silviu Gabriel","family":"Vlasceanu","sequence":"additional","affiliation":[{"name":"Department of Physiology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Thoracic Surgery, Marius Nasta Pneumology Institute, 050159 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5130-6757","authenticated-orcid":false,"given":"Denisa Maria","family":"Mitroi","sequence":"additional","affiliation":[{"name":"Doctoral School, University of Medicine and Pharmacy, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anca Lelia","family":"Riza","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genomics, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8409-5904","authenticated-orcid":false,"given":"Mara Amalia","family":"Balteanu","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, Faculty of Medicine, Titu Maiorescu University, 031593 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9976-2256","authenticated-orcid":false,"given":"Oana Maria","family":"Catana","sequence":"additional","affiliation":[{"name":"Doctoral School, University of Medicine and Pharmacy, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihai","family":"Olteanu","sequence":"additional","affiliation":[{"name":"Department of Pneumology, University of Medicine and Pharmacy, 200349 Craiova, Romania"},{"name":"Department of Pneumology, Victor Babes University Hospital, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"107325","DOI":"10.1016\/j.ijid.2024.107325","article-title":"Insights from the 2024 WHO Global Tuberculosis Report\u2014More Comprehensive Action, Innovation, and Investments Required for Achieving WHO End TB Goals","volume":"150","author":"Goletti","year":"2025","journal-title":"Int. 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