Biodegradable Manganese-Doped Calcium Phosphate Nanotheranostics for Traceable Cascade Reaction-Enhanced Anti-Tumor Therapy

Glucose oxidase (GOx) has been recognized as a "star" enzyme catalyst involved in cancer treatment in the past few years. Herein, GOx is mineralized with manganese-doped calcium phosphate (MnCaP) to form spherical nanoparticles (GOx-MnCaP NPs) by an in situ biomimetic mineralization method, followed by the loading of doxorubicin (DOX) to construct a biodegradable, biocompatible, and tumor acidity-responsive nanotheranostics for magnetic resonance imaging (MRI) and cascade reaction-enhanced cooperative cancer treatment. The GOx-driven oxidation reaction can effectively eliminate intratumoral glucose for starvation therapy, and the elevated H₂O₂ is then converted into highly toxic hydroxyl radicals via a Mn²⁺-mediated Fenton-like reaction for chemodynamic therapy (CDT). Moreover, the acidity amplification due to the gluconic acid generation will in turn accelerate the degradation of the nanoplatform and promote the Mn²⁺-H₂O₂ reaction for enhanced CDT. Meanwhile, the released Mn²⁺ ions can be used for MRI to monitor the treatment process. After carrying the anticancer drug, the DOX-loaded GOx-MnCaP can integrate starvation therapy, Mn²⁺-mediated CDT, and DOX-induced chemotherapy together, which showed greatly improved therapeutic efficacy than each monotherapy. Such an orchestrated cooperative cancer therapy demonstrated high-efficiency tumor suppression on 4T1 tumor-bearing mice with minimal side effects. Our findings suggested that the DOX-loaded GOx-MnCaP nanotheranostics with excellent biodegradability and biocompatibility hold clinical translation potential for cancer management.