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

ABSTRACT 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.