Abstract

Current therapies for prostate cancer are limited by toxicity and acquired resistance, motivating development of biocompatible nanotherapeutics. Here, Solanum nigrum L.-derived nanovesicles (SDNVs) were isolated and characterized, showing a mean diameter of 93.4 ± 0.2 nm and a particle concentration of (4.2 ± 0.4) × 10 11 /mL. SDNV uptake, antitumor activity, and safety were assessed in PC-3 and RWPE-1 cells, while efficacy and biodistribution were further evaluated in a subcutaneous PC-3 xenograft mouse model following oral administration. SDNVs were readily internalized by PC-3 cells and suppressed viability, proliferation, and migration while inducing apoptosis. Senescence and cytotoxicity were not observed in RWPE-1 cells, indicating tumor-selective activity. The underlying mechanism was further investigated by transcriptome sequencing, followed by quantitative PCR, Western blotting, and pharmacologic rescue with the p53 inhibitor pifithrin-α (PFT-α). Transcriptomic analysis revealed 5058 differentially expressed genes, and further indicated activation of the p53/p21 axis and promoted cellular senescence in PC-3 cells after SDNV treatment. In vivo, oral SDNVs significantly reduced xenograft growth and showed no evident histopathologic toxicity in major organs. Collectively, SDNVs represent a plant-derived, biocompatible nanotherapeutic platform that selectively restrains prostate cancer growth via p53/p21-mediated senescence, supporting further development of senescence-targeting SDNV-based interventions. Graphical abstract The alternative text for this image may have been generated using AI.