Chemotherapy plays an important role in treating cancers in clinic. Hypoxia-mediated chemoresistance remains a major hurdle for effective tumor chemotherapy. Herein, a new class of tLyP-1-modified dopamine (DOPA)-β-cyclodextrin (CD)-coated paclitaxel (PTX)- and manganese dioxide (MnO2 )-loaded nanoparticles (tLyP-1-CD-DOPA-MnO2 @PTX) is developed to enhance glioma chemotherapy. The nanomedicine delivered to the tumor site decomposes in response to the weak acidity and high hydrogen peroxide in the tumor microenvironment (TME), resulting in collapse of the system to release PTX and generates Mn2+ and O2 . In a rat model of intracranial glioma, tLyP-1-CD-DOPA-MnO2 @PTX can efficiently pass through the blood-brain-barrier to accumulate in tumor sites. The hypoxia in TME can be relieved via O2 generated by MnO2 and the reactive oxygen species produced by Mn2+ can kill tumor cells. The tLyP-1-CD-DOPA-MnO2 @PTX nanoparticles exert a remarkable antitumor effect by promoting apoptosis and inhibiting proliferation of tumor cells in addition to enabling real-time tumor monitoring with magnetic resonance imaging. This MnO2 -based theranostic medicine will offer a novel strategy to simultaneously enhance chemotherapy and achieve real-time imaging of therapeutic process in glioma treatment.© 2022 Wiley-VCH GmbH.