Sonodynamic therapy (SDT) and its synergistic cancer therapy derivatives, such as combined chemotherapy-SDT (chemo-SDT), are promising approaches for tumor treatment. However, the main drawbacks restricting their applications are hypoxia in tumors and the reducing microenvironment or high glutathione (GSH) levels.In this study, a hybrid metal MnO2 was deposited onto nanoparticles fabricated using poly(lactic-co-glycolic acid) (PLGA), carrying docetaxel (DTX) and the sonosensitizer hematoporphyrin monomethyl ether (HMME) (PHD@MnO2) via a one-step flash nanoprecipitation (FNP) method. Characterization and in vitro and in vivo experiments were conducted to explore the chemo-SDT effect of PHD@MnO2 and evaluate the synergetic antitumor treatment of this nanosystem.When low-power ultrasound is applied, the acquired PHD@MnO2, whether in solution or in MCF-7 cells, generated ROS more efficiently than other groups without MnO2 or those treated via monotherapy. Specifically, GSH-depletion was observed when MnO2 was introduced into the system. PHD@MnO2 presented good biocompatibility and biosafety in vitro and in vivo. These results indicated that the PHD@MnO2 nanoparticles overcame hypoxia in tumor tissue and suppressed the expression of hypoxia-inducible factor 1 alpha (HIF-1α), achieving enhanced chemo-SDT.This study provides a paradigm that rationally engineered multifunctional metal-hybrid nanoparticles can serve as an effective platform for augmenting the antitumor therapeutic efficiency of chemo-SDT.