Tumor‐Targeted Glutamine Metabolism Blocker Synergizes with TiO₂‐Au Janus Nanoparticles for Enhanced Sono‐Metabolic Antitumor Therapy

Abstract Sonodynamic therapy (SDT) is a promising therapeutic modality known for its non‐invasiveness, temporal‐spatial controllability, and deeper tissue penetration. However, the SDT treatment efficacy is still hampered by the scarcity of ideal sonosensitizers and complex tumor microenvironment (TME). To address these challenges, a sono‐metabolic nano‐composite (TiO₂‐Au@DON) using the metabolic reprogramming prodrugs of 6‐Diazo‐5‐oxo‐l‐norleucine (DON) grafted on TiO₂‐Au Janus nanoparticles (NPs) is fabricated. The coupling of TiO₂ and gold in the TiO₂‐Au@DON effectively prevents the fast recombination of excited electrons and holes under ultrasound irradiation. The result is the generation of higher levels of both type I and II reactive oxygen species (ROS) compared to pure TiO₂, which helps overcome the limitations of SDT in the hypoxic TME. Furthermore, the TiO₂‐Au Janus NPs act as nano‐carriers, delivering DON prodrugs to the tumor site. The released DON can disrupt nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) and tumor redox homeostasis by reprogramming the metabolic pathways while it intensifies the activities of immune cells. This metabolic disruption amplifies SDT‐mediated oxidative stress, resulting in the increase of tumor sensitivity to ROS through TiO₂‐Au@DON‐integrated synergistic effects of SDT and glutamine reprogramming strategies. This increased sensitivity ultimately induces robust immunogenic cell death (ICD), enhancing antitumor therapeutic efficacy and remodeling the tumor's immunosuppressive microenvironment.