Therapeutic Modulation of Inflammatory Signaling via Physalis Peruviana ‐Derived Exosomes: A Targeted Effect on IKK/NFκB/STAT1

Physalis peruviana is a carotenoid-rich fruit widely recognized for its nutritional and medicinal value, yet the molecular mechanisms underlying its bioactivity remain incompletely understood. Plant-derived extracellular vesicles have recently emerged as functional nanocarriers of bioactive metabolites; however, these vesicles from P. peruviana have not been systematically investigated. We isolated and characterized exosomes from P. peruviana fruits and evaluated their anti-inflammatory and antioxidant activities in vitro. Vesicles were isolated and characterized using transmission electron microscopy, nanoparticle tracking analysis, protein and RNA profiling, thin-layer chromatography, and untargeted metabolomics. The vesicles exhibited characteristic exosomal morphology with a mean diameter of ∼142 nm and contained proteins, miRNAs, lipids, and β-carotene as a predominant metabolite. Functional assays revealed that, at non-cytotoxic concentrations (25 µg/mL), they significantly suppressed IL-6, TNF-α, IFN-β, iNOS, and STAT1 expression in LPS-stimulated RAW 264.7 macrophages, accompanied by reduced IKK phosphorylation and inhibition of NF-κB and STAT1 transcriptional activity. In H2O2-challenged NIH3T3 fibroblasts, exosome treatment enhanced cell viability and upregulated endogenous antioxidant and mitochondrial defense markers, including CAT, SOD2, GPx4, and cytochrome c oxidase. These findings identify P. peruviana-derived exosomes as carotenoid-rich nanocarriers with anti-inflammatory and antioxidant properties, providing new mechanistic insight into the molecular actions of carotenoid-containing foods.