The ginger-derived nanovesicles-coated albumin nanoparticles induce cell death and epigenetic regulation to treat colorectal cancer

BACKGROUND: Due to the limitations of conventional cancer chemotherapy, including low bioavailability, limited indicators of therapeutic improvement, and unclear side effects, numerous laboratories have been actively engaged in the development of drug delivery systems. Here, we designed and synthesized a plant-derived ginger exosome-coated albumin nanoparticle drug delivery system (GEBSS) loaded with Shikonin (SHK) and STM2457 (a METTL3 inhibitor) and probes into the mechanism of antitumor. METHODS: We prepared and characterized GEBSS nanoparticles and evaluated their in vitro cellular uptake and targeting capabilities. The in vitro antitumor efficacy was assessed by measuring cell viability, clonogenic formation, oxidative stress, mitochondrial function, and apoptosis markers; biosafety was confirmed via a hemolysis assay. Furthermore, the ability of GEBSS to induce ICD was validated through Western blotting, ATP detection, and immunofluorescence assays, while its role in epigenetic regulation was elucidated using Dot Blot, MeRIP-qPCR, and RNA stability experiments. Finally, the in vivo antitumor effect of GEBSS was verified by intravenous administration in a nude mouse subcutaneous tumor model. RESULTS: A subsequent characterization revealed that GEBSS exhibited a concentrated size distribution around 142 nm, were efficiently absorbed by colorectal cancer (CRC) cells, and demonstrated inhibitory effects on tumor cell proliferation. In vivo experiments demonstrated excellent tumor-targeting ability, anti-tumor efficacy, and biocompatibility of GEBSS. Mechanistically, GEBSS induced apoptosis and immunogenic cell death (ICD) in tumor cells. Moreover, at the epigenetic regulation level, GEBSS suppressed cell proliferation by reducing the m6A methylation levels of immune checkpoint genes PD-L1 and CD47. CONCLUSION: This study explored the feasibility of producing naturally derived nanocarriers and, for the first time, employed a combination of SHK and STM2457 for CRC treatment, offering novel strategies and insights for nanomedicine in CRC treatment.