Ultrasound-orchestrated collapse of cancer stem cell niches through synergistic physical barrier disruption and intracellular homeostasis reprogramming

Cancer stem cells (CSCs) are a critical subpopulation within heterogeneous tumors which are largely responsible for therapeutic resistance, recurrence and metastasis. Herein, we report an ultrasound-mediated strategy based on a sono-responsive core-shell nanoplatform (MTCA) that concurrently disrupts physical barriers and reprograms intracellular homeostasis to precisely regulate and eradicate CSCs. The MTCA was engineered and surface-modified with a carbonic anhydrase IX (CAIX) inhibitor to enable selective targeting of CAIX-overexpressing CSCs and perturb their pH homeostasis. The copper-titanium dioxide shell depletes intracellular glutathione and amplifies reactive oxygen species generation under ultrasound activation, thereby overcoming CSC-associated antioxidant defenses. Meanwhile, ultrasound-induced mechanical effect transiently disrupts extracellular integrity, significantly enhancing nanoplatform penetration into CSC-enriched tumor region. This synergistic approach was found to effectively downregulate stemness-associated gene expression and suppresses CSC viability in CSC-enriched 3D tumors spheroids, which also inhibited tumor growth and metastasis in in vivo tumor models. Collectively, this study establishes an ultrasound-enabled paradigm for coordinated physical and biochemical modulation of CSC niches, offering a promising strategy to overcome CSC-driven therapeutic resistance.