STING Agonist Drug Delivery by Bacterial Extracellular Vesicles Induces Synergistic Immuno-Oncology Responses and Efficient Inhibition of Tumour Growth

Abstract

Bacterial extracellular vesicles are spherical, nanosized structures with lipid bilayer membranes and can suppress tumour growth in cancer models. However, the efficacy of some of these models is limited. One potential way to enhance their effects is by loading the bacterial vesicles with immunostimulatory molecules. We have here utilised synthetic bacterial vesicles (SyBV), previously shown to have anti-tumour effects but with reduced side effects. We hypothesized that loading SyBV with a STimulator of InterferoN Genes (STING) agonist can enhance anti-tumour effects. SyBV were generated from Escherichia coli membranes through cell breakdown induced by lysozyme and ionic stress. The produced nanovesicles encapsulated the STING agonist (SyBV^STING). SyBV^STING synergistically activated dendritic cells, leading to enhanced production of Interferon-β. Furthermore, in vivo experiments showed that immunisation with SyBV^STING synergistically suppresses melanoma and colon cancer growth by increasing the tumour infiltration of T cells. Intratumoural or subcutaneous injection of the SyBV resulted in retention in the tumour tissue over 24 h, but with some distribution to local lymph nodes. A toxicology experiment resulted in no histopathological concerns with SyBV^STING. These findings show that SyBV loaded with a STING agonist synergistically enhance anti-tumour immunity and may be a promising clinical immuno-oncology tool.

Keywords: bacterial extracellular vesicles; cancer immunotherapy; drug delivery; outer membrane vesicles; sting agonist; synthetic bacterial vesicles.