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

内容摘要

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. 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. 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. 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.