Extracellular vesicles at the immunometabolic interface in rheumatoid arthritis: evidence, mechanistic boundaries and translational opportunities

Rheumatoid arthritis (RA) is sustained by reciprocal interactions among immune, stromal, vascular and tissue-remodeling cells within a hypoxic, oxidant-rich and nutrient-competitive synovial environment. Extracellular vesicles (EVs) can transfer RNAs, proteins, lipids and other bioactive cargo between these compartments, but the RA–EV literature often invokes immunometabolic reprogramming without directly measuring metabolism. We examine evidence linking EVs, immunometabolism and RA and distinguish direct metabolic effects from metabolism-linked mechanisms, context-dependent immune phenotypes and patient-derived biomarker observations. Among the endogenous studies examined, M1-macrophage EV-associated miR-155 provides a clear example in which recipient CD4 + T-cell metabolic function was measured, including extracellular acidification, oxygen consumption, lactate excretion and intracellular ATP levels. Most other endogenous studies identify metabolism-related cargo, signaling pathways or immune phenotypes without directly establishing recipient-cell metabolic reprogramming. An engineered plant vesicle formulation loaded with spermidine also altered macrophage extracellular acidification and oxygen consumption in experimental models. These findings should be distinguished from patient-derived EV associations and from engineered systems in which an exogenous drug or catalytic material may account for the principal effect. Direct measurements of recipient-cell metabolism remain uncommon in RA–EV research. Stronger studies will require well-described EV preparations, EV- and cargo-dependence controls, functional metabolic assays, physiologically plausible dosing and validation in primary human RA systems. In the future, these approaches could inform mechanism-based patient stratification, externally validated biomarkers and targeted EV-based delivery. These are research opportunities: patient-derived EV findings have not yet established a clinically useful test, and EV-based therapy has not established clinical efficacy in RA.