Joint Laboratory of Opto-Functional Theranostics in Medicine and Chemistry, The First Hospital of Jilin University, Changchun 130021, PR China; Department of Hand and Podiatric Surgery, Orthopedics Center, The First Hospital of Jilin University, Jilin University, Changchun 130031, PR China; State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, PR China.
Department of Hand and Podiatric Surgery, Orthopedics Center, The First Hospital of Jilin University, Jilin University, Changchun 130031, PR China.
Acta Biomater. 2023 Mar 15;159:353-366. doi: 10.1016/j.actbio.2023.01.027. Epub 2023 Jan 18.
Activation of autophagy in Schwann cells (SCs) has emerged as a powerful trigger for peripheral nerve injury (PNI) repair. Lithium ion (Li) is a classical autophagy activator that plays an important role in promoting axonal extension and remyelination. However, the therapeutic window of existing lithium drugs is extremely narrow, and the adverse side effects, especially nephrotoxicity, severely limit their therapeutic value. Herein, Li-doped carbonized polymer dots (Li-CPDs) was synthesized for the first time to change the pharmacokinetics of Li from occupying epithelial sodium channels to lipid raft-mediated endocytosis. The in-vivo results confirmed that Li-CPDs could accelerate the removal of myelin debris and promote nerve regeneration via activating autophagy of SCs. Moreover, Li-CPDs exhibited almost no renal toxicity compared to that of raw lithium drugs. Thus, Li-CPDs could serve as a promising Li-based nanomedicine for PNI regeneration with improved biosafety. STATEMENT OF SIGNIFICANCE: Regardless of the fact that lithium drugs have been used in treatment of mental illness such as manic depression, the systemic side effects and renal metabolic toxicity still seriously restrict their clinical application. Since Li and Na compete for ion channels of cell membrane, the cell entry efficiency is extremely low and easily affected by body fluctuations, which seems to be an unsolvable problem. Herein, we rationally exploited the endocytotic features of CPDs to develop Li-CPDs. The Li-CPDs improved the entry pathway, greatly reduced nephrotoxicity, and inherited the biological function of Li to activate autophagy for promoting peripheral nerve regeneration. Due to the BBB-crossing property of Li-CPDs, it also showed application prospects in future research on central nervous system diseases.
自噬在施旺细胞（Schwann cells，SCs）中的激活已成为周围神经损伤（peripheral nerve injury，PNI）修复的有力触发因素。锂离子（lithium ion，Li）是一种经典的自噬激活剂，在促进轴突延伸和髓鞘再生方面发挥着重要作用。然而，现有的锂药物治疗窗极其狭窄，其不良的副作用，尤其是肾毒性，严重限制了其治疗价值。本文首次合成了锂离子掺杂的碳化聚合物点（lithium-doped carbonized polymer dots，Li-CPDs），以改变 Li 的药代动力学，使其从占据上皮钠通道转变为脂筏介导的内吞作用。体内实验结果证实，Li-CPDs 可以通过激活 SCs 的自噬来加速髓鞘碎片的清除并促进神经再生。此外，与原始锂药物相比，Li-CPDs 几乎没有肾毒性。因此，Li-CPDs 可以作为一种有前途的基于 Li 的纳米药物，用于 PNI 再生，具有改善的生物安全性。
尽管锂药物已被用于治疗躁郁症等精神疾病，但全身性副作用和肾代谢毒性仍严重限制了其临床应用。由于 Li 和 Na 竞争细胞膜的离子通道，细胞内效率极低，且容易受到身体波动的影响，这似乎是一个无法解决的问题。在本研究中，我们合理利用 CPDs 的内吞作用特性，开发了 Li-CPDs。Li-CPDs 改善了进入途径，大大降低了肾毒性，并继承了 Li 激活自噬促进周围神经再生的生物学功能。由于 Li-CPDs 具有 BBB 穿透特性，它在未来中枢神经系统疾病的研究中也具有应用前景。
