What question did this study set out to answer?

The review aims to bridge the gap between small extracellular vesicle cargo and immune dysfunction in tuberculosis–diabetes comorbidity.

April 15, 2026Open Access

Single-Cell Immune Atlases to Map Small Extracellular Vesicle Cargo in Tuberculosis–Diabetes Comorbidity: A Narrative Review and Conceptual Roadmap

Key Points

The review aims to bridge the gap between small extracellular vesicle cargo and immune dysfunction in tuberculosis–diabetes comorbidity.
Narrative review of studies from 2010 to 2026 focused on tuberculosis and diabetes mellitus.
Utilization of single-cell and multimodal immune reference atlases such as scRNA-seq and CITE-seq.
Development of frameworks for linking EV cargo to immune cell states and anatomic compartments.
Highlighting challenges in interpreting EV studies due to heterogeneous mixtures and selective cargo packaging.
Conventional analyses often overlook clinically relevant immune dysfunction in TB-DM.
Single-cell atlases could help identify specific immune cell states linked to EV cargo patterns.
Proposed frameworks aim to improve identification of biomarkers for treatment response and immunopathology.

Abstract

Tuberculosis–diabetes 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 “liquid biopsy” 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 (2010–2026), 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 “droplet-era” 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–resolved biomarkers of TB-DM immunopathology and treatment response, while prioritizing mechanistically plausible targets for host-directed intervention.

Single-Cell Immune Atlases to Map Small Extracellular Vesicle Cargo in Tuberculosis–Diabetes Comorbidity: A Narrative Review and Conceptual Roadmap

Key Points

Abstract

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