Transcriptomic profiling combined with pharmacological research of Panax notoginseng-derived nanovesicles for preliminary biocompatibility profiling and STAT5/SOCS3-driven immunomodulation in psoriasis.

BACKGROUND: Psoriasis is a chronic immune-mediated inflammatory skin disease driven by persistent IL-23/Th17 axis activation. While biologics have improved disease control, their clinical use is constrained by immunotoxicity risks and long-term safety concerns. Plant-derived extracellular vesicle-like nanoparticles (EVLNs) are being investigated as a potential biocompatible nanotherapeutic platform, yet systematic safety profiling and network-level elucidation of their immunomodulatory mechanisms remain lacking. This study integrates Systems Pharmacology, computational transcriptomic profiling, and experimental validationto evaluate the preliminary safety profiles and therapeutic mechanisms of Panax notoginseng-derived EVLNs (PN-EVLNs) in Th17-driven psoriatic inflammation.

METHODS: PN-EVLNs were isolated, characterized, and evaluated in an imiquimod-induced psoriasis-like mouse model and IL-6/TGF-β-stimulated Jurkat T cells. A systems biology framework integrating bulk RNA sequencing, public single-cell transcriptomic datasets, and pathway enrichment analysiswas employed to map treatment-responsive molecular networks and identify key regulatory modules. Computational toxicity prediction and immune pathway deconvolution were combined with histological, biochemical, and molecular validation.

RESULTS: Systems Pharmacology and transcriptomic profiling revealed that PN-EVLNs reversed psoriasis-associated inflammatory gene signatures, with computational pathway analysis identifying suppression of chemokine, IL-17, and NF-κB signaling networks. Computational safety profiling, supplemented by histological observation, suggested a favorable preliminary safety profile with no significant immunotoxic gene signatures observed in the tested models in treated models. Experimental validation confirmed that PN-EVLNs downregulated Th17-associated markers (CCR6, Tim-3) and pro-inflammatory cytokines (IL-17A, TNF-α, CCL7, CXCL10, IL-1β). Network-based mechanistic analysis pinpointed STAT5/SOCS3 as a key negative feedback regulatory module restraining Th17-driven inflammation.

CONCLUSION: Integrative Systems Pharmacology and computational safety profiling suggest that PN-EVLNs may serve as a biocompatible plant-derived nanotherapeutic with a promising preliminary safety profile. Reactivation of the STAT5/SOCS3 regulatory network underlies its immunomodulatory effects,providing a basis for the network-guided development of safer anti-psoriatic therapies using PN-EVLNs.