Layered Double Hydroxide‐Based Sonosensitizer Triggers “Paraptosis+” Multidimensional Cell Death Network for Augmented Sonodynamic Immunotherapy

Paraptosis, a caspase-independent programmed cell death pathway characterized by cytoplasmic vacuolization, presents a promising alternative for overcoming apoptosis resistance. However, its clinical translation is hampered by the low reactive oxygen species (ROS) generation efficiency and insufficient anti-tumor efficacy of existing inducers. To address these limitations, we develop defective nickel-doped ZnMo-layered double hydroxide nanosheets (DR-Ni-ZnMo-LDH) as a new inducer for paraptosis-mediated sono-immunotherapy. Under ultrasound irradiation, the DR-Ni-ZnMo-LDH exhibits excellent singlet oxygen generation activity, superior to that of all the reported sonosensitizers. Mechanistic investigations reveal that the ROS burst generated by DR-Ni-ZnMo-LDH not only effectively induces paraptosis but also concurrently activates apoptosis and ferroptosis, thereby synergistically eliminating apoptosis-resistant tumor cells. In vitro and in vivo assays confirm that this multi-modal cell death strategy elicits robust immunogenic cell death, remodels the immunosuppressive tumor microenvironment, and significantly inhibits the growth of primary and distant tumors, with inhibition rates reaching 98.44% and 88.53%, respectively. This study establishes a new material design paradigm for ROS-mediated sono-immunotherapy based on paraptosis, effectively overcoming tumor resistance and immunosuppression through multi-mechanism synergy.