Institute of New Drug Development, College of Medicine, China Medical University, Taichung 40402, Taiwan.
Functional Neurosurgery Division, Neurological Institute, Taichung Veterans General Hospital, Taichung 40705, Taiwan.
Int J Mol Sci. 2022 Jan 5;23(1):565. doi: 10.3390/ijms23010565.
Vertebral disc degenerative disease (DDD) affects millions of people worldwide and is a critical factor leading to low back and neck pain and consequent disability. Currently, no strategy has addressed curing DDD from fundamental aspects, because the pathological mechanism leading to DDD is still controversial. One possible mechanism points to the homeostatic status of extracellular matrix (ECM) anabolism, and catabolism in the disc may play a vital role in the disease's progression. If the damaged disc receives an abundant amount of cartilage, anabolic factors may stimulate the residual cells in the damaged disc to secrete the ECM and mitigate the degeneration process. To examine this hypothesis, a cartilage anabolic factor, Runx1, was expressed by mRNA through a sophisticated polyamine-based PEG-polyplex nanomicelle delivery system in the damaged disc in a rat model. The mRNA medicine and polyamine carrier have favorable safety characteristics and biocompatibility for regenerative medicine. The endocytosis of mRNA-loaded polyplex nanomicelles in vitro, mRNA delivery efficacy, hydration content, disc shrinkage, and ECM in the disc in vivo were also examined. The data revealed that the mRNA-loaded polyplex nanomicelle was promptly engulfed by cellular late endosome, then spread into the cytosol homogeneously at a rate of less than 20 min post-administration of the mRNA medicine. The mRNA expression persisted for at least 6-days post-injection in vivo. Furthermore, the Runx1 mRNA delivered by polyplex nanomicelles increased hydration content by ≈43% in the punctured disc at 4-weeks post-injection (wpi) compared with naked Runx1 mRNA administration. Meanwhile, the disc space and ECM production were also significantly ameliorated in the polyplex nanomicelle group. This study demonstrated that anabolic factor administration by polyplex nanomicelle-protected mRNA medicine, such as Runx1, plays a key role in alleviating the progress of DDD, which is an imbalance scenario of disc metabolism. This platform could be further developed as a promising strategy applied to regenerative medicine.
椎间盘退行性疾病（DDD）影响着全球数以百万计的人，是导致腰背和颈部疼痛以及随之而来的残疾的关键因素。目前，尚无任何策略从根本上解决 DDD 问题，因为导致 DDD 的病理机制仍存在争议。一种可能的机制指向细胞外基质（ECM）的稳态，椎间盘内的 ECM 合成代谢和分解代谢可能在疾病进展中起着至关重要的作用。如果受损的椎间盘接收到大量的软骨，合成代谢因子可能会刺激受损椎间盘内的残留细胞分泌 ECM，从而减轻退化过程。为了验证这一假说，在大鼠模型中，通过一种复杂的多胺基 PEG-聚电解质纳米胶束传递系统，通过 mRNA 表达软骨合成代谢因子 Runx1。该 mRNA 药物和多胺载体在再生医学中具有良好的安全性和生物相容性。还研究了体外载 mRNA 聚合物纳米胶束的内吞作用、mRNA 传递效率、水合含量、椎间盘内的椎间盘收缩和 ECM。结果表明，载 mRNA 的聚合物纳米胶束被细胞晚期内体迅速吞噬，然后在给药后 20 分钟内均匀地扩散到细胞质中。在体内，mRNA 表达至少持续 6 天。此外，与裸 Runx1 mRNA 给药相比，聚合物纳米胶束递送的 Runx1 mRNA 使注射后 4 周（wpi）时穿刺椎间盘的水合含量增加了约 43%。同时，在聚合物纳米胶束组中，椎间盘空间和 ECM 产生也得到了显著改善。本研究表明，多胺基聚合物纳米胶束保护的 mRNA 药物（如 Runx1）给药的合成代谢因子在缓解 DDD 进展方面起着关键作用，这是一种椎间盘代谢失衡的情况。该平台可以进一步开发为一种有前途的应用于再生医学的策略。
