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. [Display omitted] •A non-antimicrobial GalNAc-derived nanoplatform is developed to overcome Fn-induced chemoresistance in CRC.•PEGylation enables shield of GalNAc-mediated liver targeting for prolonged circulation and tumor accumulation.•GalNAc exposure triggered by CRC microenvironment inhibits Fn attachment to CRC cells by specific Fap2 targeting.•Chemoresistance to OxPt is reversed by blockade of Fn-host interactions and suppression of autophagy activation.