Antibacterial Fusobacterium Nucleatum-Mimicking Nanomedicine to Selectively Eliminate Tumor-colonized Bacteria And Enhance Immunotherapy Against Colorectal Cancer.

Abstract

Clinical evidence has indicated that tumor-colonizing bacteria would 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, we found that owing to the high affinity between the membrane protein Fap-2 on Fusobacterium nucleatum (F. nucleatum) and D-galactose-β (1-3)-N-acetyl-D-galactosamine (Gal-GalNAc) overexpressed on colorectal tumor cells, F. nucleatum would colonize in colorectal tumors, as evidenced by both clinical samples and animal tumor models. Notably, F. nucleatum colonized in colorectal tumors would lead to immunosuppressive tumor microenvironment, greatly reducing their responses to immune checkpoint blockade (ICB) therapy. Inspired by this finding, we designed a F. nucleatum-mimetic nanomedicine by fusing F. nucleatum cytoplasmic membrane (FM) with Colistin loaded liposomes to achieve selectively killing tumor-colonizing F. nucleatum without affecting gut microbes. As the results, the therapeutic responses of F. nucleatum-colonized tumors to ICB therapies could be successfully restored, as demonstrated in F. nucleatum-infected subcutaneous CT-26 tumor model, chemical-induced spontaneous colorectal cancer models and MC-38 tumor model. In summary, our work presented a F. nucleatum-Mimicking nanomedicine which could selectively eliminate tumor-colonized bacteria, promising for enhancing the responses of cancer immunotherapy against F. nucleatum-colonized colorectal cancer. This article is protected by copyright. All rights reserved.