MMP14-engineered biomimetic nanodrug for intratumoral antibacterial therapy suppresses colorectal cancer growth and liver metastasis

Fusobacterium nucleatum (Fn) is frequently detected at increased abundance in colorectal cancer (CRC) tissues and has been associated with tumor progression, reduced treatment responsiveness, immune escape, and poor clinical outcomes. However, whether Fn functionally contributes to colorectal cancer liver metastasis (CRLM) and can be therapeutically exploited in this context remains incompletely understood. Here, we found that Fn was enriched in CRC tissues and that higher intratumoral Fn abundance was associated with unfavorable patient outcomes. Functional experiments showed that Fn enhanced CRC cell migration, proliferation, clonogenic growth, and hepatic colonization, suggesting that Fn may participate directly in tumor progression and metastatic seeding. To integrate antitumor and intratumoral antibacterial treatment, we developed MM@IRI-MTZ, a biomimetic nanodrug consisting of a self-assembled irinotecan-metronidazole conjugated prodrug nanocore (IRI-MTZ) coated with membranes derived from matrix metalloproteinase-14 (MMP14)-overexpressing tumor cells. This design integrates chemotherapeutic and antibacterial activities within a single platform while enhancing tumor homing and stromal penetration through biomimetic membrane engineering. In vitro, MM@IRI-MTZ displayed stable physicochemical characteristics, efficient cellular uptake, cytotoxic and proapoptotic effects against CRC cells, and sustained antibacterial activity against Fn. In vivo, MM@IRI-MTZ accumulated more efficiently in tumor tissues and reduced both subcutaneous tumor growth and Fn-associated liver metastatic burden. These therapeutic effects were accompanied by decreased intratumoral Fn signals, reduced stromal collagen deposition, increased tumor cell death, and enhanced CD8 + T-cell infiltration. Transcriptomic analysis suggested that MM@IRI-MTZ attenuated inflammatory amplification, cytokine signaling, and programs involved in stromal adhesion and invasion, while increasing transcriptional features associated with antitumor immunity. No obvious histological injury was observed in major organs after MM@IRI-MTZ treatment, and overall gut microbial homeostasis was not markedly disrupted. These results support Fn as a therapeutically relevant contributor to CRC progression and liver metastasis and suggest that MM@IRI-MTZ may provide an integrated antibacterial and antitumor strategy for reducing intratumoral Fn burden within the CRC tumor microenvironment.