Abstract

Intravesical Bacillus Calmette-Guérin (BCG) perfusion is widely regarded as a standard clinical intervention for non-muscle-invasive bladder cancer. Despite its established efficacy, this treatment is associated with a high tumor recurrence rate of approximately 50%, highlighting a significant clinical challenge. To address this limitation, combination strategies integrating BCG with other antitumor modalities have emerged as a promising direction for enhancing therapeutic outcomes. In this study, we engineered a novel "super-BCG" formulation by functionalizing BCG with a copper-iron metal-organic framework (CuFe MOF). This composite system leverages the natural tropism of BCG toward bladder tumor sites to achieve targeted delivery of the MOF directly into the tumor microenvironment. Once localized, the CuFe MOF induces synergistic cuproptosis and ferroptosis, two distinct forms of regulated cell death, thereby overcoming the constraints of monotherapeutic approaches that rely on a single death mechanism. This dual induction not only promotes robust tumor cell death but also potentiates antitumor immune activation by stimulating immunogenic cell death. Furthermore, the MOF works in concert with BCG's inherent immunoadjuvant properties, resulting in a comprehensive enhancement of antitumor immunity and significantly improved immunotherapeutic efficacy. In summary, we have developed a nano-armed BCG-based therapeutic platform that integrates targeted drug delivery with dual-mode cell death induction and immune activation, offering a potent and versatile strategy for the treatment of bladder cancer.