Bacteria-driven Mitoxantrone/Ferric ions liposomes to Synergize Chemotherapy, ferroptosis and immunotherapy for robust antitumor therapy

Despite significant advancements in tumor immunotherapy, challenges including insufficient immunogenicity and immunosuppressive microenvironment continue to hinder therapeutic effect. The immunogenic cell death (ICD) enhances the tumor immune microenvironment and potentiate immunotherapy response. Certain chemotherapeutic agents can induce ICD; however, their limited immunogenicity, poor tumor-site targeting, and low tumor permeability restrict their efficacy. Herein, bacteria-driven liposomes were designed. Liposomes co-loaded with mitoxantrone (MTO) and iron ions (Fe³⁺) were engineered to leverage the hypoxia-responsive properties of Escherichia coli Nissle 1917 (EcN) for precise tumor-site targeting. In the acidic tumor environment, mitoxantrone/ferric ions liposomes (LFM) released Fe³⁺ and MTO. Intracellular Fe³⁺ is reduced to Fe²⁺, catalyzing the Fenton reaction to generate reactive oxygen species (ROS) and induce ferroptosis. Concurrently, mitoxantrone (MTO) exerts direct cytotoxic effects on tumor cells. The synergistic interplay of these mechanisms significantly enhances the immunogenicity of tumor cells, triggering ICD and subsequently activating systemic antitumor immune responses. The drug delivery system constructed in this study integrated chemotherapy, ferroptosis, and immune activation, providing an innovative and effective strategy for tumor therapy. This approach paves the way for advanced combination therapies in cancer treatment.