Metal-organic framework-mediated siRNA delivery and sonodynamic therapy for precisely triggering ferroptosis and augmenting ICD in osteosarcoma

• DOI: 10.1016/j.mtbio.2024.101053
• Publication Date: 2024-04-10T16:21:31Z
• Authors: Ningxiang Sun; Qingjian Lei; Meng Wu; Shijie Gao; Zhiqiang Yang; Xuan Lv; Renxiong Wei; Feifei Yan; Lin Cai
• Keywords: GPX4; Sonodynamic therapy

The complex genomics, immunosuppressive tumor microenvironment (TME), and chemotherapeutic resistance of osteosarcoma (OS) have resulted in limited therapeutic effects the clinic. Ferroptosis is involved progression regulated mainly by glutathione peroxidase 4 (GPX4). Small interfering RNA (siRNA)-based interference (RNAi) can precisely target any gene. However, achieving effective siRNA delivery highly challenging. Here, we fabricated a TME-responsive metal-organic framework (MOF)-based biomimetic nanosystem (mFeP@si) with siGPX4 sonodynamic therapy (SDT) to treat OS targeting ferroptosis. Under ultrasound (US) irradiation, mFeP@si achieves lysosomal escape via singlet oxygen (1O2)-mediated membrane disruption then accelerates ROS generation (GSH) depletion. Meanwhile, silences GPX4 expression binding mRNA (knockdown efficiency: >80%) leads accumulation toxic phospholipid hydroperoxides (PL-OOH), further magnifying storm triggering Notably, synergistic remarkably enhances antitumor effects, improves TME inducing potent immunogenic cell death (ICD), increases sensitivity chemotherapy-resistant cells cisplatin. Overall, this novel nanosystem, which targets ferroptosis integrating RNAi SDT, exhibits strong both vitro vivo, providing new insights for treating OS.