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/MnO2@DBCO) via a template-assisted approach, integrating MSC1094308 into ZIF-8 cores followed by MnO2 shell deposition and DBCO functionalization. In a simulated tumor microenvironment, ZIF-8 loading accelerated Mn2+ release from MnO2, increasing the cumulative release by nearly 30% within 8 h compared to pristine MnO2. Cellular assays demonstrated rapid bio-orthogonal targeting of azide-modified tumors, achieving lysosomal escape within 6 h postuptake. Subsequently, MnO2-mediated glutathione (GSH) depletion and hydroxyl radical (·OH) generation, combined with Zn2+ induced mitochondrial oxidative stress, produced cytotoxic reactive oxygen species (ROS) that triggered immunogenic cell death. Furthermore, Mn2+, Zn2+, 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 Zn2+/Mn2+ synergy, nanobomb reactivity, and ESCRT inhibition to circumvent cGAS-STING evasion, offering a promising paradigm for cancer immunotherapy.