Multichannel Sonocatalysis Amplifiers Target IDH1‐Mutated Tumor Plasticity and Attenuate Ros Tolerance to Repress Malignant Cholangiocarcinoma

Abstract Tumor adaptation‐originated tumor tolerance that compensatory mechanisms (e.g., isocitrate dehydrogenase (IDH) mutation) jointly shape is the dominant obstacle of ROS therapy. Currently, targeting a single pathway fails to fundamentally reverse the complex milieu and diminish tumor adaptation. Herein, a multichannel sonocatalysis amplifier is engineered via one‐pot gas diffusion method to attenuate IDH1‐mutated cholangiocarcinoma plasticity and tolerance to ROS therapy, wherein triptolide and IR780 are co‐loaded in DSPE‐mPEG‐modified CaCO₃ nanoparticles. Triptolide can blockade Nrf2 to cut off glutathione biosynthesis via blockading proteomic communication, and disrupt redox homeostasis to potentiate IR780‐mediated sonocatalytic ROS production. ROS‐induced mitochondria damages disrupt Ca²⁺ homeostasis and in turn aggravate ROS accumulation, which cooperates with sonocatalysis and Nrf2 blockade to reprogram mitochondrial energy and substance metabolism (e.g., adenosine triphosphatase and glutathione), hinder DNA self‐repair, and impair IDH1‐mutation‐asired tolerance. Systematic experiments support that these actions in such multichannel sonocatalysis amplifiers indeed disrupt Ca²⁺/redox homeostasis to disarm robust tumor plasticity and IDH1‐mutation‐induced tolerance to sonocatalysis therapy against IDH1‐mutated cholangiocarcinoma progression. Briefly, the sonocatalysis amplifiers pave a comprehensive avenue to reprogram tumor metabolism, target tumor vulnerability, and attenuate tumor plasticity against genomic instability‐raised treatment adaptation.