Dual enzyme-powered nanomotors for cascade-amplified sonodynamic therapy of prostate cancer

The clinical application of sonodynamic therapy (SDT) remains limited by the intrinsic hypoxic tumor microenvironment and sonosensitizer accumulation, while starvation therapy suffers from enzymatic activity in vivo . To address these challenges, we developed a cascade enzyme‑loaded extracellular vesicle platform (EV@TCG) derived from RM‑1 cells, co‑encapsulating the sonosensitizer TCPP with glucose oxidase (GOx) and catalase (CAT) via electroporation. The GOx/CAT cascade reaction depletes endogenous glucose for starvation therapy while generating oxygen that both relieve hypoxia and enhance the diffusive motion of EVs. The self‑generated oxygen serves as a substrate for TCPP‑mediated SDT, producing abundant reactive oxygen species (ROS) under ultrasound irradiation, while the enzyme‑catalysis‑enhanced cellular internalization and tumor accumulation. This synergistic mechanism improves oxidative stress, consumes glutathione and adenosine triphosphate, and elicits potent antitumor efficacy in prostate cancer models with a favorable safety profile. The EV@TCG platform thus addresses the critical limitations of hypoxia and passive diffusion, offering a robust and safe strategy for integrating cascade bio-catalysis, self‑propulsion, and sonodynamic therapy in cancer treatment.