Blocking Fusobacterium nucleatum-host cell interactions with responsive supramolecular GalNAc-derived nanoplatform for enhanced chemotherapy in colorectal cancer

Fusobacterium nucleatum (Fn) adhesion to colorectal cancer (CRC) cells is a prerequisite for chemoresistance evolution. Conventional approaches for overcoming Fn-induced chemoresistance primarily rely on antimicrobial methods, which probably cause bacterial resistance and intestinal microbiome disruption. Here, we propose a non-antimicrobial strategy to counter chemotherapy resistance of Fn-resident CRC by blocking Fn adhesion to cancer cells. Taking inspiration from the natural process of Fn colonization in CRC tissue, where the Fn lectin Fap2 binds to Gal-GalNAc displayed on CRC cells, a N-acetylgalactosamine (GalNAc)-derived nanoplatform is fabricated to disrupt this critical host-pathogen interactions. The nanoplatform (OGPA/P-C) is formulated from GalNAc-modified oligopolyethyleneimine (OEI) conjugated with oxaliplatin (OxPt) and azobenzene (AZO), along with polyethylene glycol-β-Cyclodextrin (PEG-CD) through host-guest interactions. Notably, the PEG-armed OGPA/P-C demonstrates effective accumulation in CRC tumors by evading GalNAc-mediated liver targeting, while exposing GalNAc for specific Fn targeting in response to CRC-associated azo-reductase. GalNAc exposure enables robust inhibition of Fn attachment to CRC through a Fap2-dependent competitive mechanism and overcoming chemotherapy resistance to OxPt by suppressing autophagy activation, which displays exhilarating anticancer effects against Fn-associated CRC both in vitro and in vivo. Overall, this non-lethal antiadhesion strategy holds great promise for boosting the chemotherapeutic efficacy in Fn-burdened solid tumors.