Development of a multifunctional nanotherapeutic agent with high contrast-enhanced dual-modal imaging and photothermal therapy (PTT) efficacy is of great interest. Combination of ultrasound (US) and computed tomography (CT) imaging offers high spatial resolution images, showing great potential in medical imaging. Herein, the semiconducting perfluorohexane (PFH) nanodroplets, MoS2-PFH-PLLAs, are developed by stabilizing PFH droplets with the coating shell of poly (lactic-co-glycolic acid) (PLLA) and encapsulating the droplets with photoabsorbers of ultrasmall molybdenum disulfide (MoS2) nanodots. Upon near-infrared (NIR) irradiation, the MoS2-PFH-PLLAs can absorb the NIR light and convert it into heat, which not only promotes liquid-to-gas phase transition of PFH but also triggers photothermal heating, resulting in contrast-enhanced US/CT imaging and photothermal killing effect in vitro. Furthermore, the production of microbubbles can serve as the blasting agents to collaboratively enhance PTT efficacy after NIR irradiation. When intravenously injected into tumor-bearing mice, the MoS2-PFH-PLLAs exhibit a dual-modal US/CT imaging-guided synergistically therapeutic efficacy under NIR irradiation, resulting in tumor ablation. These nanotherapeutic agents demonstrate good biocompatibility, highly contrast-enhanced US/CT imaging, and combinational enhanced PTT efficacy.Copyright © 2021. Published by Elsevier B.V.