Semiquinone Radical-Engineered Nanoparticles for Hypoxia-Adaptive and InflammationControlled Microwave-Immunotherapy...

Reactive Oxygen Species (ROS) exhibit a paradoxical dual role in tumor therapy. Tumor hypoxia restricts therapeutic ROS generation, while excessive secondary ROS post-ablation suppresses T-cell function yet promotes M1 macrophage polarization. Semiquinone radical-doped reduced polydopamine nanoparticles (PDA_red) loaded is developed with resiquimod (R848) (PDA_red@R848) via π-π stacking. Reduction enriches the nanoparticles with semiquinone radicals, enhancing dielectric properties and dipole polarization under electromagnetic effects. This nanoparticle enables the specific hydrogen radicals (H•)/ROS generation in oxygen-heterogeneous tumor under microwave irradiation. In microwave dynamics therapy (MDT) phase, PDA_red converts protons (H⁺) to H• under microwave irradiation in hypoxic regions, targeting cytochrome c and inducing tumor cell apoptosis and immunogenic cell death; PDA_red establishes an internal electric field under microwave, facilitating electron-hole separation to produce ROS and trigger ferroptosis in normoxic regions. In post-MDT phase, PDA_red's intrinsic polyphenols scavenge excess secondary ROS produced by damaged cells, alleviating immunosuppression. Compared with blank control, PDA_red@R848 increased CD4⁺/CD8⁺ T-cell infiltration (6.4-fold) and M1 macrophage polarization (2.5-fold M1/M2 ratio elevation). Pro-inflammatory cytokines are significantly reduced, and tumor volume is suppressed by 94.8%. This study proposes an innovative dual-action mechanism coordinating oxygen-adapted radical generation with secondary ROS clearance to reprogram redox/immune homeostasis for effective liver tumor eradication.