In situ-formed pH-responsive hydrogel for sequential vascular disruption and Type I sonodynamic therapy-driven PANoptosis in hypoxic tumor therapy.

PANoptosis, an inflammatory cell death integrating pyroptosis, apoptosis, and necroptosis, has emerged as a promising approach for tumor immunotherapy. Reactive oxygen species (ROS) generation is the predominant strategy for triggering PANoptosis. However, in solid tumors, the hypoxic microenvironment suppresses ROS production, thereby limiting PANoptosis induction. Herein, we present an in situ-formed pH-responsive injectable hydrogel enabling sequential delivery of 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) and Type I sonodynamic nanoparticles for hypoxic tumor immunotherapy. Upon intratumoral injection, the hydrogel gradually degrades in acidic conditions. DMXAA is released first, inducing vascular shutdown and aggravating tumor hypoxia. Subsequently, nanoparticles are liberated and, under ultrasound, generate abundant ROS via a Type I sonodynamic process, bypassing oxygen dependence. The ROS burst triggers tumor cell PANoptosis, leading to immunogenic cell death, promoting antigen release and dendritic cell maturation. In multiple hypoxic tumor models, this sequential approach achieved significant tumor regression, suppressed metastasis, and induced durable immune memory to prevent recurrence. Overall, our work presents an injectable hydrogel platform that integrates controlled drug release, Type I sonodynamic PANoptosis, and immune activation for enhanced antitumor immunotherapy.