Staphylococcus Aureus Membrane Vesicles Kill Tumor Cells Through a Caspase-1-Dependent Pyroptosis Pathway

• Published in: International journal of nanomedicine Vol. 19; pp. 4007 - 4019
• Main Authors: Li, Mengyang, Wang, Yuting, Liu, He, Huang, Xiaonan, Peng, Huagang, Yang, Yi, Hu, Zhen, Dou, Jianxiong, Xiao, Chuan, Chen, Juan, Shang, Weilong, Rao, Xiancai
• Format: Journal Article
• Language: English
• Published: New Zealand Dove Medical Press Limited 01.01.2024; Dove; Dove Medical Press
• Subjects: Animals; antares2; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Bacteria; Bacterial Outer Membrane - drug effects; Cancer; cancer therapy; Caspase 1 - metabolism; caspase-1; Cell Line, Tumor; Colon cancer; Colonic Neoplasms; Female; gsdmd; Health aspects; Luciferase; Melanoma; Melanoma, Experimental - pathology; membrane vesicles; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Original Research; Phosphate-Binding Proteins - metabolism; pyroptosis; Pyroptosis - drug effects; Staphylococcal infections; Staphylococcus aureus; Staphylococcus aureus - drug effects; Staphylococcus aureus - physiology; United Kingdom; China; GSDMD; cancer therapy; pyroptosis; Antares2; membrane vesicles; caspase-1; Staphylococcus aureus
• ISSN: 1178-2013; 1176-9114; 1178-2013
• DOI: 10.2147/IJN.S455158

Nanosized outer membrane vesicles (OMVs) from Gram-negative bacteria have attracted increasing interest because of their antitumor activity. However, the antitumor effects of MVs isolated from Gram-positive bacteria have rarely been investigated. MVs of s USA300 were prepared and their antitumor efficacy was evaluated using tumor-bearing mouse models. A gene knock-in assay was performed to generate luciferase Antares2-MVs for bioluminescent detection. Cell counting kit-8 and lactic dehydrogenase release assays were used to detect the toxicity of the MVs against tumor cells in vitro. Active caspase-1 and gasdermin D (GSDMD) levels were determined using Western blot, and the tumor inhibition ability of MVs was determined in B16F10 cells treated with a caspase-1 inhibitor. The vesicular particles of USA300 MVs were 55.23 ± 8.17 nm in diameter, and 5 μg of MVs remarkably inhibited the growth of B16F10 melanoma in C57BL/6 mice and CT26 colon adenocarcinoma in BALB/c mice. The bioluminescent signals correlated well with the concentrations of the engineered Antares2-MVs (R = 0.999), and the sensitivity for bioluminescence imaging was 4 × 10 μg. Antares2-MVs can directly target tumor tissues in vivo, and 20 μg/mL Antares2-MVs considerably reduced the growth of B16F10 and CT26 tumor cells, but not non-carcinomatous bEnd.3 cells. MV treatment substantially increased the level of active caspase-1, which processes GSDMD to trigger pyroptosis in tumor cells. Blocking caspase-1 activation with VX-765 significantly protected tumor cells from MV killing in vitro and in vivo. MVs can kill tumor cells by activating the pyroptosis pathway, and the induction of pyroptosis in tumor cells is a promising strategy for cancer treatment.