Selenium nanoparticles alleviate ulcerative colitis by regulating macrophage mitochondrial dynamics.

Ulcerative colitis (UC) progression is closely associated with aberrant macrophage polarization and mitochondrial dysfunction. Here, we explored how biogenic selenium nanoparticles (SeNPs) protect against experimental colitis, using dextran sulfate sodium (DSS)-challenged mice, together with lipopolysaccharide (LPS)-activated THP-1-derived macrophages as complementary in vivo and in vitro models. We found that selenium deficiency markedly aggravated DSS-induced intestinal barrier disruption, mucosal injury, and mitochondrial damage, underscoring the critical role of selenium homeostasis in mucosal immunity. Compared with inorganic selenium (Na2SeO3), biogenic SeNPs showed superior efficacy in alleviating colitis severity, preserving intestinal barrier integrity, restoring the intestinal stem cell niche, and promoting epithelial regeneration. Mechanistically, SeNPs shifted macrophage polarization away from the pro-inflammatory M1 state toward a more restorative profile. Transcriptomic and molecular analyses further suggested that these immunometabolic benefits were associated with preserved selenoprotein expression and peroxidase (GPx)/thioredoxin reductase (TrxR) activities, particularly restoration of the endoplasmic reticulum (ER)-resident selenoproteins selenoprotein K (SELENOK) and selenoprotein T (SELENOT), together with modulation of inositol 1,4,5-trisphosphate receptor (IP3R)-voltage-dependent anion channel 1 (VDAC1)-mediated mitochondria-associated membrane (MAM) signaling. This stabilization of inter-organelle communication effectively blunted LPS-induced cytosolic calcium overload, thereby facilitating the molecular rebalancing of mitochondrial dynamics, as reflected by reduced dynamin-related protein 1 (DRP1) and increased mitofusin 2 (MFN2) expression, and was accompanied by attenuation of reactive oxygen species (ROS) overproduction and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation. Furthermore, a Transwell co-culture system confirmed that SeNP-pretreated macrophages indirectly preserved NCM460 intestinal epithelial barrier integrity through paracrine mechanisms. Collectively, these results suggest that SeNPs may serve as a potential nanotherapeutic approach for UC by restoring intestinal homeostasis through modulation of macrophage mitochondrial dynamics and enhancement of immune-epithelial crosstalk.