Membrane calcification-reinforced tumor therapy mediated by versatile hollow manganese dioxide nanoplatform

Membrane calcification, characterized by an abnormal calcium mineral covering cell membrane, can cause aggravated hypoxia and even cell death in numerous cell lines, emerging as a new strategy for tumor therapy. Herein, based on the distinctive biological impact of cell membrane calcification, we constructed a multi-functional nanoplatform of hollow manganese dioxide (MnO₂) encapsulated with calcium carbonate (CaCO₃) and a hypoxia-activated anticancer prodrug tirapazamine (TPZ). After modification with hyaluronic acid (HA), the prepared nanoparticles HMn@CaT exhibits excellent tumor targeting and microenvironment responsiveness. Once enriched in tumor tissue, the low pH would induce the disintegration of CaCO₃ and MnO₂ to release Ca²⁺ and Mn⁴⁺, which are utilized for calcium deposition and glutathione consumption, respectively. In the presence of tumor cells rich in hydrogen peroxide, the reduced Mn²⁺ will generate highly cytotoxic ·OH through Fenton-like reactions. Meanwhile, aggravated hypoxia within tumor cells caused by membrane calcification also activates TPZ cytotoxicity, which can produce highly active and cytotoxic benzotriazinyl (BTZ) radical, leading to cell death and anti-tumor effect. The synergy of multiple effects enables the carefully designed platform of HMn@CaT to demonstrate excellent tumor inhibition both in vitro and in vivo, hence establishing a novel approach for tumor treatment.