MnO₂-Mediated cGAS-STING Signaling and Photothermal Effect Amplify Chemodynamic Therapy Induced by Fe-Based Nanoparticle in Tumor Therapy

Iron and manganese are crucial micronutrients that play vital roles in metabolism due to their redox properties. Iron is involved in ferroptosis, an iron-dependent nonapoptotic form of regulated cell death, that endows tumor cells more sensitivity to chemotherapy drugs. Manganese is a potent immune stimulator that activates cGAS-STING signaling, which plays critical roles in the initiation of antitumor immunity and conversion of cold tumor to hot tumor, by binding directly to cGAS and sensitizing cGAS to double-stranded DNA. In this study, a multifunctional nanoparticle Fe-MOF@MnO 2 @PB@HA (FMPH) was developed. We introduced Fe-based metal–organic framework (Fe-MOF) as the delivery platform, which encapsuled plinabulin (PB), a potent microtubule-destabilizing and vascular-disrupting agent that hurdles tumor growth. Fe-MOF was capped with manganese dioxide (MnO 2 ), which served to enhance the chemodynamic therapy of ferric ions by depleting endogenous glutathione (GSH) and producing cytotoxic hydroxyl radicals ( • OH). Besides, MnO 2 could elicit local hyperthermia under near-infrared (NIR) light irradiation and activate the cGAS-STING pathway to induce tumor cell death and alert the immune system. Hyaluronic acid (HA) was used to modify the nanoparticle surface so as to improve its tumor-targeting capacity and reduce systemic toxicity. Moreover, both the in vitro and in vivo experiments revealed that FMPH could efficiently suppress tumor growth and the synergistic treatment of NIR could further improve the therapeutic effect. Therefore, the multimodal effects of FMPH made it a promising nanomedical to combat cancer.