Abstract: This study aims to investigate the compositional characteristics of fresh Panax notoginseng-derived exosome-like nanovesicles (PN-ELNs) and their potential therapeutic effects on psoriasis, providing experimental evidence for plant exosome-based therapeutic strategies to ameliorate psoriasis. PN-ELNs were isolated using differential centrifugation and characterized for morphology and size distribution via transmission electron microscopy and nanoparticle tracking analysis. Their compositional profiles and enriched signaling pathways were analyzed through integrated lipidomics, proteomics, and small RNA sequencing. The in vitro effects on angiogenesis in human umbilical vein endothelial cells (HUVECs) and apoptosis in human keratinocytes (HaCaT) were evaluated. The regulatory effects on lesional symptoms, epidermal hyperplasia, angiogenesis, and immune cell subsets were observed in an imiquimod (IMQ)-induced mouse model of psoriasis. All animal experiments were conducted in accordance with the "Regulations on Laboratory Animals" issued by the National Science and Technology Commission of China and the protocol approved by the Animal Experiment Ethics Committee of Chengdu University of Traditional Chinese Medicine (approval No. 2020DL-126). Results demonstrated the successful isolation of PN-ELNs from fresh Panax notoginseng rhizomes, exhibiting a characteristic bilayer membrane structure with an average diameter of 143.9 nm. Multi-omics analyses identified 30 lipid subclasses, 196 proteins, and 6 056 miRNAs, with enriched pathways such as oxidative phosphorylation and amino acid metabolism being closely associated with psoriasis pathogenesis. PN-ELNs significantly inhibited HUVEC angiogenesis and promoted HaCaT cell apoptosis (P < 0.05). In the psoriatic mouse model, PN-ELNs significantly ameliorated skin lesions reduced psoriasis area and severity index (PASI) scores, attenuated epidermal thickening, suppressed angiogenesis, and modulated the CD4⁺/CD8⁺ immune balance. In conclusion, PN-ELNs exert anti-psoriatic effects through multi-target mechanisms (inhibiting angiogenesis, promoting keratinocyte apoptosis, and improving the immune microenvironment). This study provides the first systematic elucidation of the compositional characteristics of PN-ELNs and their anti-psoriasis potential, offering theoretical support and experimental evidence for developing novel therapeutic strategies based on plant-derived exosomes.