Ultrasound-responsive ZnMo-layered double hydroxide nanosheets induce PANoptosis for sonodynamic immunotherapy

PANoptosis, an inflammatory programmed cell death modality that combines features of pyroptosis, apoptosis, and necroptosis, can significantly enhance tumor immunogenicity. However, its therapeutic application is hindered by challenges such as inefficient reactive oxygen species (ROS) generation, uncontrolled metal ion release, and the immunosuppressive tumor microenvironment (TME). Herein, we construct an ultrasound (US)-activated TME-responsive defect-rich ZnMo-layered double hydroxide (DR-ZnMo-LDH) nanosheets for PANoptosis-mediated sonodynamic immunotherapy. The DR-ZnMo-LDH nanosheets exhibit markedly enhanced US-triggered ROS generation as well as responsive Zn 2+ release under both acidic TME and US irradiation. After modification with polyethylene glycol (PEG), in vitro assays demonstrate that DR-ZnMo-LDH-PEG simultaneously induces mitochondrial dysfunction and endoplasmic reticulum stress, leading to robust PANoptosis and immunogenic cell death. In vivo assays indicate that DR-ZnMo-LDH-PEG combined with US irradiation effectively remodels the immunosuppressive TME, elicits a systemic anti-tumor immune response, and significantly suppresses both primary and distant tumor growth, achieving inhibition rates of 96.5% and 80.6%, respectively. This study presents a “ROS-Zn 2+ ” dual-mode synergistic strategy for precise PANoptosis induction, offering a promising platform with considerable potential for translation into clinical cancer immunotherapy.