Pinellia pedatisecta Schott‐Derived Exosome‐Like Nanovesicles Promote Apoptosis in Colorectal Cancer by Regulating the Lysosome‐Mediated Mitophagy Pathway

Plant-derived exosome-like nanovesicles (ELNs) have shown potential in the treatment of various diseases. This research sought to investigate the effects of Pinellia pedatisecta Schott-derived ELNs (PPS-ELNs) on colorectal cancer (CRC). PPS-ELNs extracted from Pinellia pedatisecta Schott were characterized. CRC cell lines HCT116 and HT-29 were exposed to 10 μg/mL of PPS-ELNs. Normal colon epithelial cells FHC were treated with different concentrations of PPS-ELNs. CRC mice were treated with 12.5 or 25 mg/kg of PPS-ELNs. Subsequent experiments, including cellular uptake assay, CCK-8 assay, colony formation assay, flow cytometry, Western blot, transmission electron microscopy, LysoTracker Red staining, immunofluorescence, ELISA, in vivo imaging, TUNEL staining, immunohistochemistry, HE staining, and biochemical analysis, were conducted to explore the anti-CRC effects and potential mechanisms of PPS-ELNs. Lysosome inhibitor chloroquine was employed to elucidate the underlying mechanism in vitro. The isolated PPS-ELNs were successfully characterized. Cellular uptake of PPS-ELNs was observed in CRC cell lines. Notably, PPS-ELNs did not affect FHC cell viability, while significantly inhibiting proliferation and inducing apoptosis and mitophagy in CRC cell lines. Furthermore, PPS-ELNs induced oxidative stress and reduced lysosomal damage in HCT116 cells. The effects of PPS-ELNs on HCT116 cells were reversed by chloroquine. In CRC mice, PPS-ELNs were primarily accumulated in tumors. PPS-ELNs markedly reduced tumor growth, induced apoptosis, and decreased Ki67 expression. Additionally, PPS-ELNs decreased Gal3 expression, increased autophagosomes, and altered mitophagy-related protein levels in tumor tissues. Importantly, PPS-ELNs displayed an excellent safety profile in vivo. PPS-ELNs inhibit CRC progression through the lysosome-mediated mitophagy pathway.