Bio-hybrid Nanostructures Orchestrate Photodynamic Remodeling of the Fusobacterium nucleatum-Associated Colorectal Tumor Niche.

Abstract

The intratumoral microbiota acts as a microbial immune checkpoint in colorectal cancer (CRC), yet current strategies either kill silently without immune activation or permit bacterial rebound through incomplete targeting. Here we report a bio-hybrid assembly designed to synchronize the eradication of CRC cells and their tumor-associated Fusobacterium nucleatum. This system integrates a hemoglobin (Hb)-augmented aggregation-induced emission (AIE) photosensitizing module into cRGD-functionalized ginger-derived vesicles. This architecture couples Hb-associated oxygen availability with molecular confinement of the photosensitizer while harnessing the intrinsic anti-inflammatory components of the plant carrier to mitigate off-target toxicity. Light activation initiates a dual cascade: it induces lysosomal pyroptosis in malignant cells and disrupts key F. nucleatum pathways related to membrane transport and DNA repair. This synchronized killing elicits the coordinated release of damage- and pathogen-associated molecular patterns (PAMPs), effectively transforming an immunologically cold tumor into a robust in situ vaccine that drives dendritic cell maturation and systemic T-cell immunity. Our findings demonstrate that the integration of natural bioactivity with supramolecular engineering provides a biocompatible strategy for coordinated tumor-bacterial disruption and immunogenic remodeling of the F. nucleatum-associated tumor niche in CRC.