<p>Doxorubicin (DOX) is a widely used antitumor agent in clinical settings, while its efficacy is needed to be improved to achieve efficient tumor therapy. In this study, we utilized manganese oxide nanoparticles to deliver DOX to the tumor site and improve its efficacy. Manganese oxide nanoparticles intelligently decompose in the tumor microenvironment with a mild acidic environment, endowing them with the ability to achieve a pH-responsive DOX release. Moreover, manganese oxide nanoparticles release Mn²⁺ ions as well. The released Mn²⁺ ions catalyze the H₂O₂, which shows high levels in tumors, into hydroxyl radicals through a Fenton-like reaction and fulfill chemodynamic therapy (CDT). In vivo studies indicate that the efficacy of DOX is remarkably improved with the assistance of a Mn²⁺ ions–based CDT activity. These intelligent drug delivery systems with pH responsiveness and synergistic CDT/chemotherapy provide a potential candidate to achieve accurate tumor therapy with high efficacy.</p>