Deinoxanthin-Enriched Extracellular Vesicles from Deinococcus radiodurans Drive IL-10–Dependent Tolerogenic Programming of Dendritic Cells

Extracellular vesicles (EVs) derived from bacteria are emerging as potent bioactive carriers that affect host immunity. <i>Deinococcus radiodurans</i>, an extremophilic bacterium with strong antioxidant capacity, produces EVs enriched in deinoxanthin (DX), a carotenoid with a reactive oxygen species-scavenging activity. Here, we assessed the antioxidant activity of <i>D. radiodurans</i>-derived EVs (R1-EVs) in biochemical assays and their immunomodulatory effects on dendritic cells (DCs). R1-EVs exhibited significantly higher antioxidant activity than EVs from a DX-deficient mutant strain (ΔcrtI-EVs), consistent with DX enrichment. Bone marrow-derived DCs treated with R1-EVs in the presence of lipopolysaccharide displayed reduced expression of surface maturation markers and pro-inflammatory cytokines, while interleukin-10 (IL-10) production and antigen uptake were preserved, indicating a tolerogenic phenotype. This tolerogenic program led to decreased proliferation and cytokine production in allogeneic CD4⁺ and CD8⁺ T cells. Mechanistically, R1-EVs inhibited mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling pathways, key regulators of the DC activation. Importantly, IL-10 neutralization reversed these effects, restoring DC and T cell activation. Notably, ΔcrtI-EVs showed weaker antioxidant and immunoregulatory activities. Together, our findings identify R1-EVs as dual-functions, DX- and IL-10-dependent nanoplatform that integrates antioxidant and tolerogenic properties, with potential applications in inflammatory and autoimmune disease control.