Bio‐orthogonal Chemistry‐Facilitated Zn–Mn Double‐Layered Nanobombs Abrogate cGAS‐STING Evasion of Tumor Cells

Although cGAS‐STING immunotherapy holds immense potential, its efficacy is severely compromised by pathway evasion. To overcome this, we engineered a core‐shell bilayer nanobomb (M/ZIF/MnO 2 @DBCO) via a template‐assisted approach, integrating MSC1094308 into ZIF‐8 cores followed by MnO 2 shell deposition and DBCO functionalization. In a simulated tumor microenvironment, ZIF‐8 loading accelerated Mn 2+ release from MnO 2 , increasing the cumulative release by nearly 30% within 8 h compared to pristine MnO 2 . Cellular assays demonstrated rapid bio‐orthogonal targeting of azide‐modified tumors, achieving lysosomal escape within 6 h postuptake. Subsequently, MnO 2 ‐mediated glutathione (GSH) depletion and hydroxyl radical (·OH) generation, combined with Zn 2+ induced mitochondrial oxidative stress, produced cytotoxic reactive oxygen species (ROS) that triggered immunogenic cell death. Furthermore, Mn 2+ , Zn 2+ , and dsDNA released from damaged mitochondria cooperatively activated the cGAS‐STING pathway. Concurrently, MSC1094308 inhibited ESCRT‐mediated negative regulation, as evidenced by a ∼0.2 decrease in the p‐STING/VPS4B‐RFP colocalization coefficient, confirming the blockade of cGAS‐STING evasion. In vivo studies revealed that the nanoplatform profoundly stimulated antitumor immunity, increasing tumor‐infiltrating cytotoxic T lymphocytes approximately 8‐fold versus untreated controls after 21 days. This work establishes an integrated strategy harnessing Zn 2+ /Mn 2+ synergy, nanobomb reactivity, and ESCRT inhibition to circumvent cGAS‐STING evasion, offering a promising paradigm for cancer immunotherapy.