Chiral Cascade-Targeted Nanoassembly Eradicates Intratumoral Bacteria via Ferroptosis to Potentiate STING-Driven...

Intratumoral bacteria, particularly those residing intracellularly, are emerging as critical regulators of tumor progression and immunosuppression, yet their precise eradication and conversion of this process into an immunostimulatory signal remain a formidable challenge. Here, we report a chiral supramolecular nanoassembly, ZnO₂@CDP/Fc-DA, designed for cascade targeting of tumor cells and intracellular bacteria via d-alanine-mediated chiral matching and metabolic labeling. This system acts as a "Trojan horse", disassembling in the acidic lysosomes of tumor cells to release H₂O₂ and ferrocene-derivatized d-alanine (Fc-DA). The sustained Fenton reaction induces bacterial ferroptosis, an immunogenic form of bacterial death, which triggers the release of microbial DNA. This bacterial DNA, synergizing with the concurrently released Zn²⁺, robustly activates the cGAS-STING pathway, a cornerstone of innate immunity. Concurrently, the nanoassembly promotes immunogenic cell death (ICD) in tumor cells via ROS-mediated ferroptosis. The synergistic engagement of bacterial DNA-driven STING activation and tumor cell ICD reprograms the immunosuppressive tumor microenvironment, leading to dendritic cell maturation, cytotoxic T-cell infiltration, and profound inhibition of both primary and metastatic tumors. In contrast, the l-enantiomeric control (ZnO₂@CDP/Fc-LA) showed an inferior efficacy. This work presents a chirality-guided strategy that harnesses intratumoral bacteria as an endogenous trigger for potent antitumor immunity, establishing bacterial ferroptosis as a powerful modality for microbiome-potentiated immunotherapy.