Manganese Nanoparticles Coupled with Adjacent Single‐Atom Nanozymes for Concerted Synergistic Amplification of the cGAS‐STING Pathway and Glioblastoma Immunotherapy

ABSTRACT Glioblastoma is a highly aggressive brain tumor whose profoundly immunosuppressive tumor microenvironment (TME) compromises the efficacy of conventional therapies and immunotherapy, while insufficient activation and inefficient agonist delivery limit antitumor potential of the cGAS‐STING pathway. Herein, we design a manganese nanoparticle/adjacent single‐atom nanozyme loaded with potent STING agonist diABZI, which is further camouflaged with homologous glioma cell membranes (Mn AC/SA ‐D@M) to enable efficient blood‐brain barrier penetration and precise GBM targeting. The electronic coupling between Mn 10 ACs and neighboring Mn single‐atom sites optimizes the d‐electron density and charge distribution of Mn‐N 4 catalytic centers, thereby drastically enhancing peroxidase‐like activity and facilitating tumor‐specific hydroxyl radical generation and glutathione depletion. Such robust catalytic oxidative stress triggers ferroptosis and immunogenic cell death, accompanied by mitochondrial damage and subsequent cytoplasmic release of mitochondrial DNA, which potently activates the cGAS‐STING pathway. Meanwhile, released manganese ions (Mn 2+ ) and co‐delivered diABZI sustain and amplify STING signaling, boosting the secretion of type I interferons and proinflammatory cytokines. This integrated cascade promotes dendritic cell maturation, repolarizes tumor‐associated macrophages to antitumor M1 phenotype, and augments cytotoxic T‐cell infiltration. Consequently, the immunosuppressive TME of glioblastoma is reversed, leading to enhanced antitumor immunotherapy in orthotopic tumor models, patient‐derived organoids, and postoperative tumor recurrence settings.