Proton nanomodulators for enhanced Mn2+-mediated chemodynamic therapy of tumors via HCO3- regulation.

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.