HRP-catalyzed Mn(II) chelate-doped PDA/CaCO3 nanoparticles for tirapazamine delivery in imaging-guided tumor therapy

Tumor hypoxia limits radiotherapy and chemotherapy efficacy by promoting treatment resistance, while hypoxia-activated prodrugs (HAPs) like Tirapazamine (TPZ) face clinical failure due to insufficient tumor hypoxia. To address this challenge, we engineered HRP-catalyzed Mn(II) chelate-doped TPZ@CaCO₃/PDA-Mn@PEG nanoparticles (TCPPM NPs) that actively amplify hypoxia for potent TPZ activation. The hollow CaCO₃ core enables pH-responsive TPZ release (80% at pH 5.5), while the Mn-DopaCDTA-doped PDA shell provides enhanced T1-weighted MRI contrast ( r ₁ = 17.6 mM⁻¹s⁻¹, per Mn, 25 °C, 0.5 T), photoacoustic/ultrasound imaging, and synergistic PTT/PDT via ROS generation (4.0-fold increase, 1% O₂ conditions). In 4T1 tumor models, TCPPM NPs achieved 85% tumor reduction (vs. 45% for TPZ alone) and 45-day survival, overcoming HAP limitations through hypoxia amplification (PDA ROS O₂ consumption + 61.3 °C PTT) and calcium-mediated mitochondrial damage. This HAP-specific theranostic platform integrates precise imaging-guided therapy, presenting a breakthrough for hypoxia-targeted cancer treatment.