Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, China.
Nat Commun. 2024 Jul 9;15(1):5736. doi: 10.1038/s41467-024-50045-1.
Excessive exercise is an etiological factor of intervertebral disc degeneration (IVDD). Engineered extracellular vesicles (EVs) exhibit excellent therapeutic potential for disease-modifying treatments. Herein, we fabricate an exercise self-powered triboelectric-responsive microneedle (MN) assay with the sustainable release of optogenetically engineered EVs for IVDD repair. Mechanically, exercise promotes cytosolic DNA sensing-mediated inflammatory activation in senescent nucleus pulposus (NP) cells (the master cell population for IVD homeostasis maintenance), which accelerates IVDD. TREX1 serves as a crucial nuclease, and disassembly of TRAM1-TREX1 complex disrupts the subcellular localization of TREX1, triggering TREX1-dependent genomic DNA damage during NP cell senescence. Optogenetically engineered EVs deliver TRAM1 protein into senescent NP cells, which effectively reconstructs the elimination function of TREX1. Triboelectric nanogenerator (TENG) harvests mechanical energy and triggers the controllable release of engineered EVs. Notably, an optogenetically engineered EV-based targeting treatment strategy is used for the treatment of IVDD, showing promising clinical potential for the treatment of degeneration-associated disorders.
过度运动是椎间盘退变（IVDD）的病因之一。工程细胞外囊泡（EVs）在疾病修饰治疗方面表现出极好的治疗潜力。在此，我们设计了一种运动自供电摩擦电响应微针（MN）分析系统，用于 IVDD 修复的光遗传工程 EVs 的可持续释放。在机械方面，运动促进衰老核髓核（NP）细胞中胞质 DNA 感应介导的炎症激活（IVD 稳态维持的主要细胞群），从而加速 IVDD。TREX1 作为一种关键的核酸内切酶，TRAM1-TREX1 复合物的解体破坏了 TREX1 的亚细胞定位，在 NP 细胞衰老过程中引发 TREX1 依赖性基因组 DNA 损伤。光遗传工程 EV 将 TRAM1 蛋白递送至衰老的 NP 细胞，有效地重建了 TREX1 的消除功能。摩擦纳米发电机（TENG）收集机械能并触发工程 EV 的可控释放。值得注意的是，基于光遗传工程 EV 的靶向治疗策略被用于 IVDD 的治疗，为治疗与退化相关的疾病提供了有前景的临床潜力。
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