Dual-targeted manganese-doped carbon dots activate the cGAS-STING pathway and immunogenic cell death for potent glioblastoma immunotherapy.

Glioblastoma (GBM) remains poorly responsive to immunotherapy due to restricted brain delivery and a profoundly immunosuppressive "cold" microenvironment. Here, we report ultrasmall manganese-doped carbon dots enriched with surface amino and carboxyl groups (Mn-CDs) as a self-adjuvanted nanotherapeutic that integrates dual targeting with a synergistic immune cascade. Mn-CDs exploit LAT1-mediated transport to traverse the blood-brain barrier and preferentially accumulate in glioma tissue, while their intrinsic positive surface potential drives mitochondrial tropism via the mitochondrial membrane potential. Once localized to mitochondria, mixed-valence Mn centers catalyze Fenton-like reactions, amplifying oxidative stress and inducing mitochondrial depolarization and ultrastructural disruption. This organelle-localized stress is coupled to robust activation of the cGAS-STING-TBK1-IRF3 axis, leading to elevated IFN-I signaling and proinflammatory chemokine production. In parallel, Mn-CDs elicit immunogenic cell death, as evidenced by calreticulin (CRT) exposure, HMGB1 release, and extracellular ATP emission, thereby promoting dendritic cell maturation and cytotoxic T-cell infiltration. In orthotopic syngeneic GBM models, Mn-CDs remodel the immunosuppressive tumor microenvironment, suppress intracranial tumor progression, and prolong survival with favorable biosafety. Collectively, this work establishes a dual-targeted Mn-based carbon nanoplatform that converts GBM toward an immune-responsive state through convergent cGAS-STING activation and ICD-driven immune priming.