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Updated: Jul 16, 2025
A Preclinical Mouse Model of Osteosarcoma to Define the Extracellular Vesicle-mediated Communication Between Tumor and Mesenchymal Stem Cells
Published on: May 6, 2018
In vivo self-assembly and delivery of VEGFR2 siRNA-encapsulated small extracellular vesicles for lung metastatic
Lingfeng Yu1, Gentao Fan1, Qingyan Wang2
1Department of Orthopedics, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, 210002, China.
Abstract:
The prognosis of lung metastatic osteosarcoma (OS) remains disappointing. siRNA-based gene silencing of VEGFR2 is a promising treatment strategy for lung metastatic OS, but there is a lack of safe and efficient delivery systems to encapsulate siRNAs for in vivo administration. This study presented a synthetic biological strategy that remolds the host liver with synthesized genetic circuits for efficient in vivo VEGFR2 siRNA delivery. After being taken-up by hepatocytes, the genetic circuit (in the form of a DNA plasmid) reprogrammed the liver to drive the autonomous intrahepatic assembly and encapsulation of VEGFR2 siRNAs into secretory small extracellular vesicles (sEVs), thus allowing for the transport of self-assembled VEGFR2 siRNAs towards the lung. The results showed that our strategy was superior to the positive medicine (Apatinib) for OS lung metastasis in terms of therapeutic efficacy and toxic adverse effects and may provide a feasible and viable therapeutic solution for lung metastatic OS.
Insights
This study developed a novel liver-based gene therapy for osteosarcoma lung metastasis. The engineered liver delivers VEGFR2 siRNA via extracellular vesicles, showing improved efficacy and reduced toxicity compared to current treatments.
Area of Science:
- Oncology
- Gene Therapy
- Synthetic Biology
Background:
- Lung metastatic osteosarcoma (OS) has a poor prognosis.
- Effective in vivo delivery of siRNA therapeutics for VEGFR2 gene silencing is challenging.
- Current treatments for metastatic OS have limitations in efficacy and safety.
Purpose of the Study:
- To develop a safe and efficient in vivo delivery system for VEGFR2-targeting siRNA in osteosarcoma.
- To utilize a synthetic biological approach by reprogramming hepatocytes for siRNA production and delivery.
- To evaluate the therapeutic potential of this novel strategy against lung metastatic OS.
Main Methods:
- Engineered a DNA plasmid containing a genetic circuit for intrahepatic siRNA synthesis and packaging.
- Delivered the genetic circuit to hepatocytes for autonomous assembly of VEGFR2 siRNA into small extracellular vesicles (sEVs).
- Investigated the transport of sEVs carrying VEGFR2 siRNA to the lungs and assessed therapeutic efficacy and toxicity in a preclinical model.
Main Results:
- The synthetic liver-remodeling strategy successfully produced and secreted VEGFR2 siRNA encapsulated in sEVs.
- The delivered sEVs effectively targeted lung metastases in osteosarcoma models.
- The novel approach demonstrated superior therapeutic efficacy and a better safety profile than the positive control drug, Apatinib.
Conclusions:
- Reprogramming the liver with synthetic genetic circuits offers a viable platform for in vivo siRNA delivery.
- This strategy provides a promising therapeutic solution for lung metastatic osteosarcoma.
- The method shows potential for improved treatment outcomes with reduced adverse effects in metastatic OS.
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