A hollow nanozyme-based multifunctional platform enhances sonodynamic–chemodynamic-induced ferroptosis for cancer therapy

Ferroptosis, a novel form of cell death driven by lipid peroxides (LPO) accumulation, holds promise for personalized cancer therapy. However, its efficacy is constrained by the tumor microenvironment (TME), which is characterized by hypoxia, insufficient endogenous hydrogen peroxide (H₂O₂), and glutathione (GSH) overabundance. To address these limitations, we developed a multifunctional nanoplatform, HMnO₂-VC@mPEG-Ce6 (HMVC), which integrates sono-chemodynamic strategies to induce synergistic ferroptosis in prostate cancer. The therapeutic superiority of HMVC stems from three coordinated mechanisms. Firstly, HMnO₂ catalyze H₂O₂ decomposition to generate oxygen (O₂), alleviating tumor hypoxia and amplifying the sonodynamic effect of chlorin e6 (Ce6). Secondly, vitamin C (VC) sustains H₂O₂ production <i>via</i> chemodynamic therapy (CDT), driving a burst of reactive oxygen species (ROS). Thirdly, GSH-triggered reduction of Mn⁴⁺ to Mn²⁺ depletes GSH reserves and suppresses glutathione peroxidase 4 (GPX4) activity. These cascading actions disrupt the ROS-GPX4 equilibrium, leading to irreversible LPO accumulation and subsequent ferroptosis. Our work establishes a generalizable nanotechnology paradigm to overcome TME barriers and achieve precise ferroptosis regulation, offering a transformative strategy for cancer treatment.