Ultrasound-mediated intra-/extracellular dual intervening effect combined with all-trans retinoic acid for cancer stemness inhibition

Cancer stem cells (CSCs), characterized by robust self-renewal capacity and varied differentiation potential, are considered pivotal in the ineffectiveness of cancer therapy. Some strategies targeting CSCs may exhibit limited efficacy due to the rigid extracellular matrix (ECM) in tumor region that still maintains stemness through mechanosensitive pathways. Herein, an ultrasound (US)-mediated intra/extracellular dual intervening strategy was developed for effective tumor stemness inhibition. Specifically, a kind of US-responsive nanodroplets (PAP@Lipid) co-loaded with all-trans retinoic acid (ARTA) and paclitaxel (PTX) are constructed via one step emulsification process. Thereinto, the encapsulated ARTA is beneficial to CSC stemness and chemoresistance, and the perfluorohexane (PFH) core of nanodroplets enables local US enhancement through acoustic droplet vaporization (ADV) effect. Moreover, the enhanced US effect can initiate reactive oxygen species (ROS) generation and aldehyde dehydrogenase (ALDH) downregulation, synergistically diminishing CSC populations in combination with ARTA. More importantly, it also simultaneously destroys the ECM, rendering a softened tumor with reduced stemness level and enhanced vulnerability to PTX, thereby promoting therapeutic effect. The in vivo antitumor evaluations demonstrate the remarkable inhibiting effect of This US-mediated intra/extracellular intervening strategy on both 4T1 and chemoresistant tumors, providing an encouraging paradigm for combating refractory cancers.