Proton Nanomodulators for Enhanced Mn 2+ -mediated Chemodynamic Therapy of Tumors via HCO 3 − Regulation

Abstract Background Mn²⁺-mediated chemodynamic therapy (CDT) has been emerged as a promising cancer therapeutic modality that relies heavily on HCO₃⁻ level in the system. Although the physiological buffers (H₂CO₃/HCO₃⁻) provide certain amounts of HCO₃⁻, the acidity of the tumor microenvironment (TME) would seriously affect the HCO₃⁻ ionic equilibrium (H₂CO₃ ⇌ H⁺ + HCO₃⁻). As a result, HCO₃⁻ level in the tumor region is actually insufficient to support effective Mn²⁺-mediated CDT. Results In this study, a robust nanomodulator MnFe₂O₄@ZIF-8 (PrSMZ) with the capability of in situ self-regulation HCO₃⁻ is presented to enhance therapeutic efficacy of Mn²⁺-mediated CDT. Under an acidic tumor microenvironment, PrSMZ could act as a proton sponge to shift the HCO₃⁻ ionic equilibrium to the positive direction, significantly boosting the generation of the HCO₃⁻. Most importantly, such HCO₃⁻ supply capacity of PrSMZ could be finely modulated by its ZIF-8 shell thickness, resulting in a 1000-fold increase in reactive oxygen species (ROS) generation. Enhanced ROS-dependent CDT efficacy is further amplified by a glutathione (GSH)-depletion ability and the photothermal effect inherited from the inner core MnFe₂O₄ of PrSMZ to exert the remarkable antitumor effect on mouse models. Conclusions This work addresses the challenge of insufficient HCO₃⁻ in the TME for Mn²⁺-mediated Fenton catalysts and could provide a promising strategy for designing high-performance Mn²⁺-mediated CDT agents to treat cancer effectively.