Sun Jiajia, Gu Jia, Ding Yan, Tu Xinyi, Cai Xiaohui, Jiang Baochun, Chen Zhongping
Institute of Special Environmental Medicine, Nantong University, Nantong, People's Republic of China.
Department of Hematology, The Third Affiliated Hospital of Nanjing Medical University, Changzhou, People's Republic of China.
Mater Today Bio. 2025 Jun 26;33:102025. doi: 10.1016/j.mtbio.2025.102025. eCollection 2025 Aug.
Neuropathic pain is a devastating experience for patients and its treatment remains challenging. Dorsal root ganglion (DRG) is currently an important therapeutic target and DRG-targeted analgesic delivery through systemic injection is however not reported. Herein, a disintegrin and metalloproteinase protein 8 (ADAM8), a membrane-anchored protein primarily recognized as a cancer biomarker, is found to be de novo and persistently upregulated in the DRG neurons in spared nerve injury (SNI) and chemotherapy-induced neuropathic pain (CINP), two neuropathic pain models with distinct mechanisms. We thus designed a DRG-targeted delivery strategy using lipid nanoparticles (LNPs), aiming to effectively deliver conventional analgesics to the DRG to improve analgesic effect through blocking pain signal transduction from the periphery to central nervous system. and results revealed that LNPs extended the duration of action of the free analgesic from less than 6 h to more than 24 h and particularly, showed therapeutic superiority over conventional liposomes, achieved by their good structural stability for a more sustained release kinetics. After functionalized with a specific ADAM8 inhibitory peptide, the intravenously injected LNPs facilitated analgesic accumulation in the DRG in SNI and CINP. As a result, the LNPs significantly improved the intensity of action for pain relief in a single or repeated treatments, which ultimately relieved pain-related psychiatric comorbidities, while not causing latent systemic toxicities. To our best knowledge, it is the first example of nanoparticles-based DRG-targeted delivery strategy through systemic injection in treating neuropathic pain.
神经性疼痛对患者来说是一种极具破坏性的体验，其治疗仍然具有挑战性。背根神经节（DRG）目前是一个重要的治疗靶点，然而，尚未有通过全身注射进行DRG靶向镇痛给药的报道。在此，我们发现，在两种机制不同的神经性疼痛模型—— spared nerve injury（SNI）和化疗诱导的神经性疼痛（CINP）中，一种主要被视为癌症生物标志物的膜锚定蛋白——去整合素和金属蛋白酶8（ADAM8），在DRG神经元中从头持续上调。因此，我们设计了一种使用脂质纳米颗粒（LNPs）的DRG靶向给药策略，旨在通过阻断从外周到中枢神经系统的疼痛信号转导，将传统镇痛药有效递送至DRG，以提高镇痛效果。 结果显示，LNPs将游离镇痛药的作用持续时间从不到6小时延长至超过24小时，特别是，与传统脂质体相比，LNPs具有更好的结构稳定性和更持续的释放动力学，从而表现出治疗优势。用特定的ADAM8抑制肽功能化后，静脉注射的LNPs促进了镇痛药在SNI和CINP的DRG中的蓄积。结果，LNPs在单次或重复治疗中显著提高了缓解疼痛的作用强度，最终缓解了与疼痛相关的精神共病，同时未引起潜在的全身毒性。据我们所知，这是首例通过全身注射基于纳米颗粒的DRG靶向给药策略治疗神经性疼痛的研究。
