Multifunctional nanodrug for simultaneously combating chemoresistance and immunosuppression in Fusobacterium nucleatum-associated colorectal cancer

Fusobacterium nucleatum (Fn) infection in colorectal cancer (CRC) induces chemoresistance and creates an immunosuppressive tumor microenvironment, compromising the efficacy of conventional chemotherapy. To address these challenges, a multifunctional MPLO@HA nanodrug was developed by conjugating metformin (Met), oxaliplatin (OxPt), and lauric acid (LA) onto oligomethyleneimine, subsequently complexed with hyaluronic acid (HA). The MPLO@HA nanodrug is designed to target Fn-infected CRC, offering multiple mechanisms for enhanced therapeutic outcomes. The nanodrug features a multi-stimuli responsive structure that enables precise and controlled release at the tumor site, responsive to pH, glutathione, and hyaluronidase levels. The enhanced positive charge of self-assembled nanodrug combined with Met effectively eradicates both extracellular and intracellular Fn, overcoming Fn-induced chemoresistance. Furthermore, incorporating Met improves the efficacy of chemotherapy by sensitizing CRC cells to treatment. The immunomodulatory properties of the MPLO@HA nanodrug promote immunogenic cell death, repolarize macrophages from the M2 to the M1 phenotype, and reduce the levels of regulatory T cells and myeloid-derived suppressor cells. By integrating antimicrobial, chemotherapeutic, and immunomodulatory capabilities, the MPLO@HA nanodrug offers a promising and comprehensive approach to combating Fn-induced chemoresistance and immunosuppression in CRC. This strategy could also provide a foundation for developing treatments for other cancers associated with bacterial infections.