Natural exosome-like nanovesicles from Salvia chinensis Benth induce ferroptosis to suppress hepatocellular carcinoma progression via AMPK/Nrf2/xCT axis.

To isolate exosome-like nanovesicles from Salvia chinensis Benth (SCENs), and expire the mechanisms SCENs induce ferroptosis in hepatocellular carcinoma (HCC) in vivo and in vitro, thereby offering a novel therapeutic option for HCC. SCENs were isolated from fresh Salvia chinensis Benth by ultra-centrifugation and gradient sucrose solution purification methods. The physicochemical properties of SCENs were characterized through NTA, TEM and LC-MS/MS. RNA-Seq was used to evaluate SCENs in regulating mRNA expression in vitro. The be uptake of SCENs by HepG2, MHCC97H, HuH-7, and HL-7702 cells was assessed by DIO fluorescent probes. The anti-proliferative, anti-migratory, anti-invasive, and pro-apoptotic effects of SCENs on HCC were evaluated in vitro. Experiments were conducted in vitro and vivo to investigate the role of SCENs in inducing ferroptosis in HCC and determine which mechanism is associated. The biosafety of SCENs was assessed in vitro and vivo. SCENs were uptake by HepG2, MHCC97H, and HuH-7 cells. SCENs exhibited anti-proliferative, anti-migratory, anti-invasive, pro-apoptotic, and ferroptosis-inducing effects on HCC. Both in vitro experiments and HCC models demonstrated that SCENs-induced ferroptosis in HCC was associated with the AMPK/Nrf2/xCT axis. Additionally, SCENs displayed excellent biosafety profiles in vitro and vivo. SCENs demonstrate significant anti-HCC effects, excellent biosafety, and accessibility, showcasing their potential in the development and application of anti-HCC nanotherapy.