Immuno-enhancing nanoplatform: Hollow manganese dioxide-integrated polydopamine/graphitic carbon nitride enables sustained STING/PDT synergy

Abstract The clinical application of stimulator of interferon genes (STING) agonists in cancer immunotherapy has been limited by inefficient systemic delivery, off-target toxicity and the immunosuppressive tumor microenvironment. In this study, we developed a multifunctional nanoplatform featuring a hollow manganese dioxide (H-MnO2) as a core sequentially coated with polydopamine (PDA) and graphitic carbon nitride (g-C3N4) layers, termed as HMPC. HMPC mediates antitumor immunity through three coordinated mechanisms. (i) H-MnO2 decomposes in response to glutathione (GSH), releasing Mn2+ to activate STING pathway, and catalyzing H2O2 to produce oxygen, effectively alleviating hypoxia-mediated immunosuppression in the tumors. (ii) The hollow structure enhances electron transfer between g-C3N4 and PDA, enabling robust reactive oxygen species (ROS) generation under 660 nm irradiation, which synergizes with Mn2+-mediated Fenton-like reactions for cooperative ROS amplification. (iii) The ROS burst potently induces immunogenic cell death (ICD), releasing double-stranded DNA (dsDNA) that cooperates with Mn2+ to sustain STING activation. In vivo, HMPC triggers a STING-dependent immune signaling cascade, enhancing tumor infiltration of CD8+ T cells, CD4+ T cells, natural killer (NK) cells, and M1-type macrophages, thereby promoting tumor eradication. By spatiotemporally coupling STING activation with photodynamic therapy, HMPC demonstrates multimodal responsiveness and synergistic efficacy, offering a potential strategy to overcome current barriers in cancer immunotherapy.