Ultrasound-Triggered O2 Bombs: Perfluorobromooctane-Loaded Defect-Rich Metal-Organic framework for enhanced Sono-Immunotherapy

Sonodynamic therapy (SDT) has emerged as a promising strategy for treating tumors owing to its non-invasiveness and high tissue-penetrating depth. Improving the efficiency of electron-hole separation of sonosensitizers and alleviation of the hypoxic tumor microenvironment remain major challenges. Metal-organic frameworks (MOFs) have greatly potential in SDT application, however, exploring new sonosensitizers with high reactive oxygen species (ROS) generation and improving the efficacy through a synergistic effect in combination with other therapeutic modalities remain major challenges. Furthermore, the immunosuppressive tumor microenvironment (TME) is characterized by hypoxia, which limit the efficacy of O2-dependent cancer treatments including SDT and immunotherapy. Herein, we fabricated a defect-rich titanium-based MOFs using propionic acid-mediated self-templated hierarchical etching. Reductive platinum nanoparticles were embedded onto the surface of MOFs to enhance the spatial separation of electron-hole pairs and improve the quantum yield of ultrasound-generated singlet oxygen (1O2). Finally, perfluorobromooctane was encapsulated in the MOFs to function as an oxygen carrier to develop an oxygen self-feeding nanosensitizer. In vitro and in vivo assays demonstrated that this nanoplatform could produce high levels of 1O2 under ultrasound irradiation, which led to enhanced SDT. Moreover, this nanoplatform also relieved the immunosuppressive TME by overcoming hypoxia and enhancing immunogenic cell death to promote the infiltration of tumor-specific cytotoxic T cells into the immunologically “cold” tumor. Therefore, combination of nanoplatform-mediated SDT with anti-PDL1 antibodies effectively inhibited the primary tumors, as well as the metastatic tumors. This study provides an insightful strategy for improving SDT and broadens the application of MOF-based sonosensitizers for sono-immunotherapy.