Mitochondria-targeted piezoelectric catalyst regulate pyroptosis and efferocytosis for enhancing the osteosarcoma immunogenic death

The immunosuppressive microenvironment (TME) of osteosarcoma (OS) results in an unsatisfactory conventional therapeutic effect. Conventional chemotherapy-induced apoptosis is unsuccessful to fully activate anti-tumor immunity as it fails to release Tumor-Associated Antigens (TAAs) and promotes efferocytosis of Tumor-Associated Macrophages (TAMs). In this study, we propose to remodel TME by inducing OS cells to immunogenic cell death, including pyroptosis and necroptosis induced by efferocytosis inhibition of TAMs. Specifically, we constructed a piezoelectric catalyst, BFO@CaO₂-TPP (BCT), which targets mitochondria. Under ultrasound, BCT generated reactive oxygen species (ROS) by enhancing the Fenton reaction and released Ca 2+ to trigger mitochondrial calcium overload, which synergistically activated the caspase-3/GSDME nonclassical pyroptosis pathway and prompted the release of proinflammatory molecules from tumor cells. At the same time, BCT disrupts mitochondrial oxidative phosphorylation (OXPHOS) in TAMs, inhibits their efferocytotic capacity. More importantly, TAMs facilitate the elevation of the GSDME express and TNF/TNFR1 interaction in osteosarcoma cells, favoring pyroptosis and necroptosis. Simultaneous endogenous and exogenous regulation is ultimately transforms the ‘cold’ TME into a ‘hot’ state. Patient-derived organoid-based validation confirmed the translational potential of this strategy.