Construction of Z-Scheme MOF-on-MOF Heterostructures for Mitochondria-Targeted Sonodynamic Therapy.

Metal-organic framework (MOF)-based nano-sonosensitizers are promising for antitumor sonodynamic therapy (SDT). Under ultrasound (US) irradiation, MOF-based sonosensitizers can generate reactive oxygen species (ROS), thereby exerting cytotoxic effects on tumor cells. However, their low electron-hole (e^-/h⁺) separation efficiency and limited tumor-targeting capability hinder the therapeutic efficacy of SDT. In this study, these challenges were addressed by developing a MOF-on-MOF Z-scheme heterojunction GaMOF/TiMOF (GM/TM) to enable mitochondria-targeted SDT. Research on gallium (Ga)-based materials in the field of antitumor treatment is continuously advancing, particularly in targeted therapy and combination therapy. The GM/TM heterojunction was constructed by epitaxially growing GaMOF on the surface of NH₂-MIL-125 (TiMOF), forming a structure that effectively enhances charge transfer and prevents rapid e^-/h⁺ recombination, significantly enhancing ROS generation and apoptosis under US irradiation. Additionally, the presence of surface Ga³⁺ enables efficient mitochondrial targeting in tumor cells, leading to altered membrane permeability, mitochondrial iron overload, and the initiation of ferroptosis via lipid peroxidation. These synergistic effects collectively result in potent antitumor efficacy. This study conceptually introduces the MOF-on-MOF heterojunction as a multifunctional sonosensitizer for mitochondria-targeted tumor therapy, offering a reference for the development of SDT and providing insights into the bioavailability and potential applications of gallium-based materials in antitumor treatment. STATEMENT OF SIGNIFICANCE: In this study, we developed a MOF-on-MOF composite ultrasound-sensitive platform targeting mitochondria to improve the efficacy of SDT in complex tumor lesions. It integrated apoptosis and ferroptosis to enhance anti-tumor SDT via ultrasound. The Z-scheme heterostructure sonosensitizer GaMOF/TiMOF significantly enhanced ROS generation under ultrasound and accumulated in mitochondria, making them the primary target for SDT. Moreover, the damage to mitochondrial function caused by GaMOF/TiMOF led to an imbalance of endogenous iron and oxidative stress, inducing mitochondrial-associated ferroptosis. This, in turn, triggered lipid peroxidation in conjunction with high levels of ROS generated by ultrasound, significantly enhancing the anti-tumor effects of SDT. This work provided a new strategy for efficient and safe sonosensitizer modification and proposed an innovative mitochondrial-targeted therapeutic approach.