Drug-Loaded Bacterial Outer Membrane Vesicles Eradicate Intratumoral Fusobacterium nucleatum to Enhance Colorectal Cancer Treatment

Abstract Colorectal cancer (CRC) represents one of the most commonly diagnosed malignancies in which Fusobacterium nucleatum (Fn) infiltration critically drives tumor progression by fostering an immunosuppressive tumor microenvironment (TME) that compromises immunotherapy efficacy. Outer membrane vesicles (OMVs) originating from Escherichia coli Nissle 1917 offer an attractive tumor-targeting drug delivery system, combining intrinsic immunostimulatory properties with drug-loading capacity. We therefore developed an OMV-based dual-function system coencapsulating 5-fluorouracil (5-Fu) and metronidazole (MTZ), designated 5-Fu/MTZ@OMVs. In vitro, this system effectively eliminated both CT26 cells and Fn while promoting DC maturation and driving repolarization of M2 macrophages toward M1 as well as N2 neutrophils toward N1. In vivo, upon administration to an Fn-colonized CT26 model, the system homed to tumors, reduced the Fn burden, and inhibited tumor growth, demonstrating its bactericidal and antitumor efficacy. Notably, it reversed immunosuppressive TME by promoting DC maturation, M1 macrophage, and N1 neutrophil polarization, which enhanced the recruitment and functional activation of CD4+ and CD8+ T cells within the tumor. Thus, by integrating bactericidal, antitumor, and immune remodeling activities into a single OMV platform, our strategy constitutes a viable therapeutic approach for Fn-associated CRC.

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