超声协同物理屏障破坏与细胞内稳态重编程瓦解癌症干细胞生态位的新策略

Abstract

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.