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Porous Silicon Microparticles for Delivery of siRNA Therapeutics
Published on: January 15, 2015
Metal-organic framework-mediated siRNA delivery and sonodynamic therapy for precisely triggering ferroptosis and
Ningxiang Sun1, Qingjian Lei1, Meng Wu2
1Department of Spine Surgery and Musculoskeletal Tumor, Zhongnan Hospital of Wuhan University, 168 Donghu Street, Wuchang District, Wuhan, Hubei, 430071, China.
Abstract:
The complex genomics, immunosuppressive tumor microenvironment (TME), and chemotherapeutic resistance of osteosarcoma (OS) have resulted in limited therapeutic effects in the clinic. Ferroptosis is involved in tumor progression and is regulated mainly by glutathione peroxidase 4 (GPX4). Small interfering RNA (siRNA)-based RNA interference (RNAi) can precisely target any gene. However, achieving effective siRNA delivery is highly challenging. Here, we fabricated a TME-responsive metal-organic framework (MOF)-based biomimetic nanosystem (mFeP@si) with siGPX4 delivery and sonodynamic therapy (SDT) to treat OS by targeting ferroptosis. Under ultrasound (US) irradiation, mFeP@si achieves lysosomal escape via singlet oxygen (1O2)-mediated lysosomal membrane disruption and then accelerates ROS generation and glutathione (GSH) depletion. Meanwhile, siGPX4 silences GPX4 expression by binding to GPX4 mRNA and leads to the accumulation of toxic phospholipid hydroperoxides (PL-OOH), further magnifying the ROS storm and triggering ferroptosis. Notably, synergistic therapy remarkably enhances antitumor effects, improves the immunosuppressive TME by inducing potent immunogenic cell death (ICD), and increases the sensitivity of chemotherapy-resistant OS cells to cisplatin. Overall, this novel nanosystem, which targets ferroptosis by integrating RNAi and SDT, exhibits strong antitumor effects both in vitro and in vivo, providing new insights for treating OS.
Insights
This study introduces a novel nanosystem for osteosarcoma treatment, combining RNA interference and sonodynamic therapy to induce ferroptosis. This approach enhances antitumor effects and overcomes chemotherapy resistance.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Osteosarcoma (OS) presents challenges due to complex genomics, an immunosuppressive tumor microenvironment (TME), and drug resistance.
- Ferroptosis, a regulated cell death pathway, is implicated in tumor progression and is primarily controlled by glutathione peroxidase 4 (GPX4).
- Effective delivery of small interfering RNA (siRNA) for gene silencing remains a significant hurdle in cancer therapy.
Purpose of the Study:
- To develop a TME-responsive metal-organic framework (MOF)-based biomimetic nanosystem (mFeP@si) for targeted ferroptosis induction in OS.
- To integrate siRNA delivery (siGPX4) with sonodynamic therapy (SDT) for synergistic antitumor effects.
- To investigate the potential of this nanosystem in overcoming chemotherapy resistance and modulating the tumor microenvironment.
Main Methods:
- Fabrication of a TME-responsive MOF-based biomimetic nanosystem (mFeP@si) for siGPX4 delivery.
- Utilizing ultrasound (US) irradiation to trigger lysosomal escape and reactive oxygen species (ROS) generation.
- Employing siGPX4 to silence GPX4 expression, leading to ferroptosis induction.
- Evaluating synergistic therapeutic effects, TME modulation, and chemotherapy sensitivity in vitro and in vivo.
Main Results:
- The mFeP@si system effectively delivered siGPX4 and, upon US irradiation, induced lysosomal escape and amplified ROS generation.
- GPX4 silencing by siGPX4 led to phospholipid hydroperoxide accumulation and triggered ferroptosis.
- The synergistic therapy demonstrated significant antitumor efficacy, enhanced immunogenic cell death (ICD), and improved sensitivity to cisplatin in resistant OS cells.
- The nanosystem showed strong antitumor effects both in vitro and in vivo.
Conclusions:
- The novel nanosystem effectively targets ferroptosis by integrating RNA interference and sonodynamic therapy for osteosarcoma treatment.
- This approach offers a promising strategy to overcome therapeutic limitations in osteosarcoma, including drug resistance and immunosuppressive TME.
- The developed biomimetic nanosystem provides new insights for developing advanced cancer therapies.
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