Coordination‐Guided Therapeutic‐Coating Oncolytic Bacteria Enabling Pyroptosis Amplification and Synergistic Breast Tumor Suppression

Abstract Treatment for triple‐negative breast cancer (TNBC) is severely hampered by factors such as the lack of specific molecular targets and high tumor immunosuppression. Benefiting from the natural tumor‐targeting properties of microbes, oncolytic bacteria‐mediated antitumor therapy has shown great clinical potential in TNBC treatment but suffers from poor bioavailability and limited monotherapy efficacy. Herein, a coordination‐guided therapeutic‐coating strategy for oncolytic bacteria to synergistically enhance pyroptosis against is developed TNBC. By introducing calcium ions and the classical antitumor agent mitoxantrone (MTO) onto the surface of Salmonella typhimurium VNP20009, MTO@Ca‐VNP20009 via intermolecular coordination interactions is constructed. The surface coating of VNP20009 reduces the immunogenicity of oncolytic bacteria during in vivo circulation. Given the tumor‐targeting ability of VNP20009, MTO can be synchronously delivered to tumors. The responsive intratumoral release of MTO, in combination with VNP20009, potentiates tumor cell pyroptosis, triggering a robust immune response. Therapeutic outcomes demonstrate significantly inhibited orthotopic tumor growth and reduced distal and lung metastases in both subcutaneous and metastatic TNBC murine models. This intermolecular force‐guided therapeutic‐coating strategy holds significant potential for enhancing the bioavailability and therapeutic efficacy of oncolytic bacteriotherapy.