Department of Orthopedics, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, 210002, China.
Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023, China.
Cell Death Dis. 2023 Sep 22;14(9):626. doi: 10.1038/s41419-023-06159-3.
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.
肺转移骨肉瘤（OS）的预后仍然不容乐观。VEGFR2 的 siRNA 基因沉默是治疗肺转移 OS 的一种很有前途的治疗策略，但缺乏安全有效的输送系统来包裹 siRNA 进行体内给药。本研究提出了一种合成生物学策略，用合成的遗传电路重塑宿主肝脏，以实现高效的体内 VEGFR2 siRNA 递释。在被肝细胞摄取后，该遗传电路（以 DNA 质粒的形式）重新编程肝脏，以驱动 VEGFR2 siRNA 的自主肝内组装和封装到分泌型小细胞外囊泡（sEVs）中，从而允许自组装的 VEGFR2 siRNA 向肺部运输。结果表明，与阳性药物（阿帕替尼）相比，该策略在治疗骨肉瘤肺转移方面具有更好的疗效和更小的毒副作用，为肺转移骨肉瘤提供了一种可行的治疗方案。
