Zhao Zhenyu, Ruan Huitong, Chen Aopan, Xiong Wei, Zhang Mingzhu, Cai Ming, Cui Wenguo
Department of Orthopaedics, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, No.301 Middle Yanchang Road, Shanghai 200072, China.
Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China.
Research (Wash D C). 2023 Sep 1;6:0221. doi: 10.34133/research.0221. eCollection 2023.
Genetic engineering technology can achieve specific gene therapy for a variety of diseases, but the current strategy still has some flaws, such as a complex system, single treatment, and large implantation trauma. Herein, the genetic engineering injectable hydrogels were constructed by ultrasonic technology for the first time to realize in vivo ultrasound-triggered in situ cross-linking and cell gene transfection, and finally complete in situ gene therapy to promote bone reconstruction. First, ultrasound-triggered calcium release was used to activate transglutaminase and catalyze the transamidation between fibrinogen. Simultaneously, liposome loaded with Zinc-finger E-box-binding homeobox 1 (ZEB1) gene plasmid (Lip-ZEB1) was combined to construct an ultrasound-triggered in situ cross-linked hydrogels that can deliver Lip-ZEB1. Second, ultrasound-triggered injectable hydrogel introduced ZEB1 gene plasmid into endothelial cell genome through Lip-ZEB1 sustained release, and then acted on the ZEB1/Notch signal pathway of cells, promoting angiogenesis and local bone reconstruction of osteoporosis through genetic engineering. Overall, this strategy provides an advanced gene delivery system through genetic engineered ultrasound-triggered injectable hydrogels.
基因工程技术可以实现针对多种疾病的特异性基因治疗，但目前的策略仍存在一些缺陷，如系统复杂、单一治疗方式以及植入创伤大等问题。在此，首次通过超声技术构建了基因工程可注射水凝胶，以实现体内超声触发的原位交联和细胞基因转染，最终完成原位基因治疗以促进骨重建。首先，利用超声触发的钙释放来激活转谷氨酰胺酶并催化纤维蛋白原之间的转酰胺反应。同时，将负载锌指E盒结合同源框1（ZEB1）基因质粒的脂质体（Lip-ZEB1）相结合，构建一种能够递送Lip-ZEB1的超声触发原位交联水凝胶。其次，超声触发的可注射水凝胶通过Lip-ZEB1的持续释放将ZEB1基因质粒导入内皮细胞基因组，然后作用于细胞的ZEB1/Notch信号通路，通过基因工程促进骨质疏松症的血管生成和局部骨重建。总体而言，该策略通过基因工程超声触发的可注射水凝胶提供了一种先进的基因递送系统。
