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 (HO), and glutathione (GSH) overabundance. To address these limitations, we developed a multifunctional nanoplatform, HMnO-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, HMnO catalyze HO decomposition to generate oxygen (O), alleviating tumor hypoxia and amplifying the sonodynamic effect of chlorin e6 (Ce6). Secondly, vitamin C (VC) sustains HO production chemodynamic therapy (CDT), driving a burst of reactive oxygen species (ROS). Thirdly, GSH-triggered reduction of Mn to Mn 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.