Breaking the Depth Barrier: Dual‐Activated Radical Storm from a Natural Product‐Based Nanoplatform for Spatiotemporally Controlled Deep Tumor Sonodynamic Therapy

Abstract Natural active ingredients from traditional Chinese medicine offer promising avenues for cancer therapy due to their unique bioactivities and low systemic toxicity. Nevertheless, their clinical translation is often hampered by poor aqueous solubility, rapid systemic clearance, and limited tumor penetration. To overcome these challenges, a multifunctional nanoplatform ( TTQ‐Arte NPs ) based on Artesunate (Arte) is developed, a semisynthetic derivative of artemisinin known for its oxygen‐independent cytotoxic effects via generation of superoxide anions (•O 2 − ) and carbon‐centered radicals (•C) through Fe 2 ⁺‐mediated cleavage of its endoperoxide bridge. In this system, Arte is covalently linked to TTQ , a aggregation‐induced emissionorganic sonosensitizer, and self‐assembled into nanosonosensitizers using DSPE‐PEG2000. This platform employs a dual activation mechanism: ultrasound triggers the generation of singlet oxygen ( 1 O 2 ), while intracellular Fe 2 ⁺ facilitates Arte activation, collectively generating a synergistic “radical storm” comprising •O 2 − , •C, 1 O 2 , and lipid peroxyl radicals (LOO•). Ultrasound‐induced cavitation enhances tissue penetration (>300 µm), leading to more homogeneous drug distribution. The TTQ‐Arte system demonstrates potent reactive oxygen species generation, extensive multi‐organelle disruption, and robust tumor suppression in both 3D tumor spheroids and 4T1 murine tumor models. These findings highlight a clinically translatable strategy for precise, natural product‐based sonodynamic therapy targeting deep‐seated solid tumors.