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Chemotherapy is the first\u2010line treatment for brain tumors but low efficiency of drugs in crossing the blood\u2013brain barrier (BBB) and drug resistance related to tumor hypoxia thwart its efficacy. Herein, a theranostic nanodrug (iRPPA@TMZ\/MnO) is developed by incorporating oleic acid\u2010modified manganese oxide (MnO) and temozolomide (TMZ) into a polyethylene glycol\u2010poly(2\u2010(diisopropylamino)ethyl methacrylate\u2010based polymeric micelle containing internalizing arginine\u2010glycine\u2010aspartic acid (iRGD). The presence of iRGD provides the nanodrug with a high capacity of crossing the BBB and penetrating the tumor tissue. After accumulation in glioma, the nanodrug responds to the tumor microenvironment to simultaneously release TMZ, Mn<jats:sup>2+<\/jats:sup>, and O<jats:sub>2<\/jats:sub>. The released TMZ induces tumor cell apoptosis and the released Mn<jats:sup>2+<\/jats:sup> causes intracellular oxidative stress that kill tumor cells via a Fenton\u2010like reaction. The O<jats:sub>2<\/jats:sub> produced in situ alleviates tumor hypoxia and enhances the chemotherapy\/chemodynamic therapeutic effects against glioma. The Mn<jats:sup>2+<\/jats:sup> can also serve as a magnetic resonance imaging (MRI) contrast agent for tumor imaging during therapy. 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