Natural panax notoginseng-derived nanovesicles trigger multiple cell death mechanisms and reprogram chemokine signaling to impede oral squamous cell carcinoma progression.

Oral squamous cell carcinoma (OSCC) remains one of the most aggressive malignancies of the oral epithelium, with limited therapeutic options effectively targeting both tumor growth and metastasis. Plant-derived nanovesicles have emerged as natural, biocompatible nanomedicines with potential applications in cancer therapy. Here, we systematically screened nanovesicles from ten medicinal plants and identified Panax notoginseng-derived nanovesicles (PnNVs) as the most potent inhibitors of OSCC. PnNVs exhibited favorable safety profiles and intrinsic tumor-homing ability, selectively accumulating in orthotopic tongue tumors. In vivo, they markedly suppressed primary tumor growth and lymphatic metastasis. Mechanistically, PnNVs disrupted redox homeostasis by inhibiting the p38-MAPK/NRF2 signaling pathway, thereby inducing ferroptosis, autophagy, and PANoptosis. In addition, PnNVs impaired cancer cell migration by modulating chemokine-associated signaling pathways critical for tumor dissemination. Multi-omic analyses further revealed synergistic contributions of RNA cargos and metabolite components to their multi-target anticancer efficacy. Collectively, our findings establish PnNVs as a natural, multifunctional therapeutic candidate with dual anti-proliferative and anti-metastatic activity, providing a promising preclinical strategy for OSCC treatment.