Protein-assisted synthesis of chitosan-coated minicells enhance dendritic cell recruitment for therapeutic immunomodulation within pulmonary tumors

Abstract

The efficacy of cancer therapies is significantly compromised by the immunosuppressive tumor milieu. Herein, we introduce a previously unidentified therapeutic strategy that harnesses the synergistic potential of chitosan-coated bacterial vesicles and a targeted chemotherapeutic agent to activate dendritic cells, thereby reshaping the immunosuppressive milieu for enhanced cancer therapy. Our study focuses on the protein-mediated modification of bacterium-derived minicells with chitosan molecules, facilitating the precise delivery of Doxorubicin to tumor sites guided by folate-mediated homing cues. These engineered minicells demonstrate remarkable specificity in targeting lung carcinomas, triggering immunogenic cell death and releasing tumor antigens and damage-associated molecular patterns, including calreticulin and high mobility group box 1. Additionally, the chitosan coating, coupled with bacterial DNA from the minicells, initiates the generation of reactive oxygen species and mitochondrial DNA release. These orchestrated events culminate in dendritic cell maturation via activation of the stimulator of interferon genes signaling pathway, resulting in the recruitment of CD4+ and CD8+ cytotoxic T cells and the secretion of interferon-β, interferon-γ, and interleukin-12. Consequently, this integrated approach disrupts the immunosuppressive tumor microenvironment, impeding tumor progression. By leveraging bacterial vesicles as potent dendritic cell activators, our strategy presents a promising paradigm for synergistic cancer treatment, seamlessly integrating chemotherapy and immunotherapy.