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

Abstract

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.

Statement of significance

Fusobacterium nucleatum (Fn) infection in colorectal cancer (CRC) induces chemoresistance and creates an immunosuppressive tumor microenvironment, severely compromising treatment efficacy. Current therapies face challenges in addressing these issues due to the complex interactions between bacterial infection and tumor development. Our study introduces a multifunctional nanodrug, MPLO@HA, which integrates metformin, oxaliplatin, lauric acid, and hyaluronic acid into a multi-responsive nanodrug system. This nanodrug simultaneously combats bacterial infection, chemoresistance, and immunosuppression in Fn-associated CRC. MPLO@HA demonstrates synergistic effects by eradicating both extracellular and intracellular Fn, enhancing chemosensitivity, and modulating the tumor immune microenvironment. This comprehensive approach offers a promising strategy to overcome Fn-induced treatment barriers, potentially improving outcomes for patients with Fn-infected CRC and opening new avenues in bacteria-associated cancer therapy.