Rehmannia-derived nanovesicles hijack the cell cycle to suppress oral squamous cell carcinoma via PI3K-AKT pathway blockade.

Oral squamous cell carcinoma (OSCC) remains a highly prevalent malignancy with limited improvement in 5-year survival rates, underscoring the need for novel therapeutic strategies. Plant-derived nanovesicles (PDNVs) have emerged as a new class of bioactive nanoparticles with intrinsic anticancer properties. In this study, we successfully isolated Rehmannia-derived nanovesicles (RDNVs) from fresh Rehmannia glutinosa roots and evaluated their antitumor efficacy and biosafety in OSCC. Characterization revealed that RDNVs exhibit typical exosome-like morphology and size distribution. In vitro, RDNVs were efficiently internalized by OSCC cells in a time- and concentration-dependent manner, leading to significant inhibition of cell proliferation via G1-phase arrest, as well as suppression of migration and invasion. In vivo, systemically administered RDNVs accumulated in tumor tissues and markedly suppressed tumor growth in a tongue orthotopic OSCC mouse model, with no observable systemic toxicity. Mechanistically, RDNVs exert their antitumor effects by downregulating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway, thereby disrupting cell cycle progression. These findings identify RDNVs as a promising natural nanotherapeutic candidate for OSCC and provide a novel research paradigm bridging traditional herbal resources and modern nanomedicine.