Antibacterial <i>Fusobacterium nucleatum</i>‐Mimicking Nanomedicine to Selectively Eliminate Tumor‐Colonized Bacteria and Enhance Immunotherapy Against Colorectal Cancer

Abstract

Clinical evidence indicates that tumor-colonizing bacteria can be closely related to the tumor development and therapeutic responses. Selectively eliminating bacteria within tumors may be an attractive approach to enhance cancer treatment without additional side effects. Herein, it is found that, owing to the high affinity between the membrane protein Fap-2 on Fusobacterium nucleatum and d-galactose-β (1-3)-N-acetyl-d-galactosamine (Gal-GalNAc) overexpressed on colorectal tumor cells, F. nucleatum can colonize in colorectal tumors, as evidenced by both clinical samples and animal tumor models. Notably, F. nucleatum colonized in colorectal tumors can lead to an immunosuppressive tumor microenvironment, greatly reducing their responses to immune checkpoint blockade (ICB) therapy. Inspired by this finding, an F. nucleatum-mimetic nanomedicine is designed by fusing F. nucleatum cytoplasmic membrane (FM) with Colistin-loaded liposomes to achieve selective killing of tumor-colonizing F. nucleatum without affecting gut microbes. As a result, the therapeutic responses of F. nucleatum-colonized tumors to ICB therapies can be successfully restored, as demonstrated in an F. nucleatum-infected subcutaneous CT-26 tumor model, chemically induced spontaneous colorectal cancer models, and MC-38 tumor model. In summary, this work presents an F. nucleatum-mimicking nanomedicine that can selectively eliminate tumor-colonized bacteria, which is promising for enhancing the responses of cancer immunotherapy against F. nucleatum-colonized colorectal cancer.