A Manganese-Based Nanodriver Coordinates Tumor Prevention and Suppression through STING Activation in Glioblastoma

Glioblastoma (GBM), the most prevalent and aggressive primary malignant brain tumor, exhibits profound immunosuppression and demonstrates a low response rate to current immunotherapy strategies. Manganese cations (Mn²⁺) directly activate the cGAS/STING pathway and induce the unique catalytic synthesis of 2'3'-cGAMP to facilitate type I IFN production, thereby enhancing innate immunity. Here, a telodendrimer and Mn²⁺-based nanodriver (PLHM) with a small size is developed, which effectively target lymph nodes through the blood circulation and exhibit tumor-preventive effects at low doses of Mn²⁺ (3.7 mg kg^-1). On the other hand, the PLHM nanodriver also exhibits apparent antitumor effects in GBM-bearing mice via inducing in vivo innate immune responses. The combination of PLHM with doxorubicin nanoparticles (PLHM-DOX NPs) results in superior inhibition of tumor growth in GBM-bearing mice due to the synergistic potentiation of STING pathway functionality by Mn²⁺ and the presence of cytoplasmic DNA. These findings demonstrate that PLHM-DOX NPs effectively stimulate innate immunity, promote dendritic cell maturation, and orchestrate cascaded infiltration of CD8 cytotoxic T lymphocytes within glioblastomas characterized by low immunogenicity. These nanodivers chelated with Mn²⁺ show promising potential for tumor prevention and antitumor effects on glioblastoma by activating the STING pathway.