Sonogenic malate depleting modulator for tumor metabolic reprogramming and antitumor immune activation

The malate/aspartate shuttle is essential for maintaining mitochondrial membrane potential (MMP) and supporting tumor metabolism and survival. However, developing effective, controllable strategies to manipulate malate metabolism in vivo remains a challenge. Here, we report a sonogenically activated malate depletion modulator (MDM), GO/BCT:Mn, which integrates graphene oxide (GO) with Ca/Mn co-doped barium titanate (BCT:Mn) nanoparticles, enabling simultaneous metabolic and immune modulation under ultrasonic stimulation. Mechanistic studies reveal ultrasound triggers spatial charge separation in GO/BCT:Mn, generating reductive electrons and oxidative holes. Electrons drive the reduction of H⁺ to H₂, lowering MMP and providing a gas therapy effect, whereas oxidative holes convert NADH to NAD⁺, suppressing malate synthesis and disrupting the malate/aspartate shuttle, thereby impairing mitochondrial integrity. These synergistic actions induce mitochondrial depolarization, autophagy, and apoptosis. In a murine colon cancer model, treatment with GO/BCT:Mn markedly suppressed tumor cell proliferation (Ki67) and angiogenesis (VEGF, CD31), while promoting apoptosis (TUNEL, Caspase-3). Transcriptomic and flow cytometry analyses further revealed activation of immune-related pathways, accompanied by increased infiltration of CD4⁺/CD8⁺ T cells and mature dendritic cells, indicating that metabolic perturbation synergistically enhances anti-tumor immunity. Collectively, this work establishes a precise ultrasound-responsive nanoplatform that couples redox-mediated metabolic disruption with immune activation, offering a promising strategy for integrated metabolism-immune cancer therapy.