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

Mn.sup.2+-mediated chemodynamic therapy (CDT) has been emerged as a promising cancer therapeutic modality that relies heavily on HCO.sub.3.sup.- level in the system. Although the physiological buffers (H.sub.2CO.sub.3/HCO.sub.3.sup.-) provide certain amounts of HCO.sub.3.sup.-, the acidity of the tumor microenvironment (TME) would seriously affect the HCO.sub.3.sup.- ionic equilibrium (H.sub.2CO.sub.3 â H.sup.+ + HCO.sub.3.sup.-). As a result, HCO.sub.3.sup.- level in the tumor region is actually insufficient to support effective Mn.sup.2+-mediated CDT. In this study, a robust nanomodulator MnFe.sub.2O.sub.4@ZIF-8 (PrSMZ) with the capability of in situ self-regulation HCO.sub.3.sup.- is presented to enhance therapeutic efficacy of Mn.sup.2+-mediated CDT. Under an acidic tumor microenvironment, PrSMZ could act as a proton sponge to shift the HCO.sub.3.sup.- ionic equilibrium to the positive direction, significantly boosting the generation of the HCO.sub.3.sup.-. Most importantly, such HCO.sub.3.sup.- 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 MnFe.sub.2O.sub.4 of PrSMZ to exert the remarkable antitumor effect on mouse models. This work addresses the challenge of insufficient HCO.sub.3.sup.- in the TME for Mn.sup.2+-mediated Fenton catalysts and could provide a promising strategy for designing high-performance Mn.sup.2+-mediated CDT agents to treat cancer effectively.