An siENPP1‐Delivering Bimetallic MOF Nanocomplex Enables Triple Activation of the cGAS‐STING Pathway for Synergistic Triple‐Negative Breast Cancer Therapy

ABSTRACT Triple‐negative breast cancer (TNBC) is associated with poor prognosis due to its highly heterogeneous tumor immune microenvironment and the lack of actionable molecular targets, which collectively limit the efficacy of current therapies. To address these challenges, PEI/siENPP1@Mn‐ZIF‐8 (PEMZ) is reported, an integrated gene–chemodynamic–immune nanocomplex that activates the cyclic GMP‐AMP synthase‐stimulator of interferon genes (cGAS‐STING) pathway through a previously unattainable triple‐activation mechanism. PEMZ efficiently encapsulates siENPP1, protects it from degradation, and enables acid‐responsive cytosolic release, resulting in sustained ectonucleotide pyrophosphatase/phosphodiesterase 1 ( ENPP1 ) silencing and accumulation of tumor‐derived cyclic 2′,3′‐GMP‐AMP (cGAMP). Simultaneously, the Mn 2+ /Zn 2+ ions released from the trienzyme‐mimetic nanocomplex, which exhibits peroxidase‐, catalase‐, and glutathione peroxidase‐like activities, amplify intracellular reactive oxygen species, deplete glutathione, and trigger mitochondrial dysfunction. This coordinated redox disruption induces immunogenic cell death and further enhances STING signaling. In vitro and in vivo studies demonstrate that PEMZ markedly suppresses TNBC proliferation and metastasis, promotes dendritic cell maturation, and increases intratumoral CD8 + T‐cell infiltration, achieving potent tumor inhibition with minimal systemic toxicity. This work establishes PEMZ as a mechanistically integrated nano‐immunotherapy platform, offering a promising and broadly applicable strategy for the precision treatment of TNBC and other ENPP1‐overexpressing cancers.