Mn(III)-Derived MnO2-x Passivated Graphene Quantum Dots for Tumor-Specific Chemo-Immunotherapy Through Triggering Ferroptosis and Activating cGAS-STING Pathway.

Chemotherapy is still widely used for combating solid tumors, yet its bottleneck is often associated with off-target toxicity and weak immune activation. Herein, we report a TME-activatable nanoplatform based on MnO2-x to load graphene quantum dot (GQD/MnO2-x) for tumor-specific chemo-immunotherapy. By comparing MnCl2-, MnF3-, and KMnO4-derived MnO2-x, we find that Mn(III)-derived MnO2-x exhibits the highest OV content (27.2%) and GQD loading efficiency (61.35%). Specifically, coordination between pyrrolic N in GQDs and Mn3+ suppresses Mn(III) disproportionation, promoting OV formation and improving GQD encapsulation. MnO2-x carrier passivates the DNA damage effect of GQDs against normal cells while undergoing GSH-triggered degradation in tumors to release GQDs and Mn ions. Upon tumor-specific disassembly, released GQDs bind the DNA major groove and induce DNA damage for improved chemotherapy. Concurrently, Mn4+-mediated GSH depletion promotes ferroptosis and reverses the immunosuppressive TME, whereas released Mn2+ activates cGAS-STING pathway to promote DC maturation and activate T cells. This cascade amplification of antitumor immune response mediated by GQD/MnO2-x achieves effective inhibition effect on the growth of primary and distant tumors without recurrence. Overall, this work highlights activity passivation engineering for the utilization of TME-responsive nanoplatforms for tumor-specific chemotherapy amplified immunotherapy through triggering ferroptosis and activating cGAS-STING pathway.