Intervertebral disc degeneration is an essential pathological basis for a variety of spinal degenerative diseases, and the pharmacological intervention strategies used in the clinic usually only alleviate the pain-related symptoms, but fail to reverse or delay the degenerative diseases. Therefore, in-depth exploration of the key regulatory mechanisms of intervertebral disc degeneration and the construction of effective regenerative repair strategies are of great clinical significance. Studies have shown that intervertebral disc degeneration is associated with DNA damage and activation of cytoplasmic DNA sensing-related pathways. However, the role of TREX1 as a nuclease mediating cytoplasmic damaging DNA clearance in degenerating intervertebral disc cells is unclear. Previous literature, using proteomics technology, discovered that endoplasmic reticulum-associated protein TRAM1 is a potential chaperone molecule that regulates the clearance function of TREX1. Catabolic disruption of the TRAM1-TREX1 protein complex drives TREX1 translocation to the nucleus and triggers TREX1 nuclease activity, which ultimately accelerates the activation of cytoplasmic DNA sensing-associated pathways and leads to a shift in the inflammatory phenotype of senescent nucleus pulposus cells and intervertebral disc degeneration.
Based on the discovery of the key mechanism of nucleus pulposus cell senescence during disc degeneration, Prof. Xuhui Sun and Prof. Zhen Wen from the Institute of Functional Nano & Soft Materials at Soochow University, together with Prof. Cao Yang at Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, innovatively proposed a triboelectric-responsive TRAM1 protein delivery system for precise and targeted disc repair. In order to effectively restore the elimination function of TREX1 and achieve efficient repair of intervertebral disc degeneration, the concept of optically reversible protein-protein interactions was applied to load TRAM1 protein into extracellular vesicles and design a self-driven friction electro-responsive microneedle system. Using coated microneedles as carriers and controlled delivery platforms, the system can deliver the TRAM1 protein-loaded extracellular vesicles on the surface of microneedle electrodes to aged nucleus pulposus cells in a highly efficient and electrically responsive controllable manner using the pulsed electrical stimulation generated by a wearable triboelectric stimulator. This system ultimately reestablished the removal of damaged DNA molecules from cytoplasmic DNA molecules by TREX1 protein in the degenerating nucleus pulposus cells. The novel design of this system enables precise, targeted and responsive repair of disc degeneration with high efficiency. This work provides a highly efficient therapeutic strategy for the repair of disc degeneration and shows great clinical potential for the treatment of degeneration-related diseases. The results were published in Nature Communications under the title 'Self-powered triboelectric-responsive microneedles with controllable release of optogenetically engineered extracellular vesicles for intervertebral disc degeneration repair'.
Fig 1. Design and working mechanism of triboelectric-responsive TRAM1 protein delivery system
Fig 2. Self-powered triboelectric-responsive microneedle system enables the repair process of intervertebral disc degeneration
Link to paper: https://www.nature.com/articles/s41467-024-50045-1
Title: Self-powered triboelectric-responsive microneedles with controllable release of optogenetically engineered extracellular vesicles for intervertebral disc degeneration repair
Authors: Weifeng Zhang#, Xuan Qin#, Gaocai Li#, Xingyu Zhou#, Hongyang Li, Di Wu, Yu Song, Kangcheng Zhao, Kun Wang, Xiaobo Feng, Lei Tan, Bingjin Wang*, Xuhui Sun*, Zhen Wen*, Cao Yang*
Editor: Danting Xiang, Xin Du