Engineered RVG-exosomes-mediated delivery of siRNAs targeting NMDAR alleviates orofacial neuropathic pain by suppressing central sensitivity

IF 4 2区医学 Q1 CLINICAL NEUROLOGY

Journal of Pain Pub Date : 2025-06-05 DOI:10.1016/j.jpain.2025.105457

Yan-Yan Zhang , Yue-Ling Li , Qin-Xuan Song , Ya-Ting Yi , Yu-Heng Feng , Yi-Ke Li , Cheng Zhou , Chun-Jie Li , Fei Liu , Jie-Fei Shen

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引用次数: 0

Abstract

Orofacial neuropathic pain (NP) is a common complication in oral clinical practice that severely affects quality of life. However, NP does not currently receive effective medications. Engineered exosomes have great potential as drug delivery systems for treating diseases. Here, patch clamp techniques showed that the deficiency of N-methyl-D-aspartic acid receptor (NMDAR) subunits 2A and 2B reversed the spontaneous excitatory postsynaptic current (sEPSC) frequency and neuronal excitability in the spinal trigeminal nucleus caudalis (SpVc) after injury, which is an effective therapeutic target for NP. Hence, we successfully employed exosomes (EXOs) modified with the nervous system-specific rabies virus glycoprotein (RVG) peptide, which exhibited excellent targeting ability towards N2a-Neuro cells and SpVc tissue. RVG-EXOs loaded with siRNAs of NR2A/B efficiently targeted SpVc neurons, further reducing neuronal excitability and relieving the orofacial NP. Taken together, our study investigated the role of NR2A/B in central nociceptive sensitization and suggested that RVG-EXOs-mediated delivery of siRNAs targeting NR2A and NR2B was effective for orofacial NP treatment.

Perspective

This study investigated the crucial role of NMDAR in central sensitization of the SpVc after nerve injury. In this study, we innovatively explored a central targeted drug delivery system based on engineered RVG-EXOs, providing a basis for targeted minimally invasive treatments of orofacial NP.

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工程化rvg外泌体介导的靶向NMDAR的sirna递送通过抑制中枢敏感性减轻口面部神经性疼痛。

口面神经性疼痛是口腔临床常见的并发症，严重影响生活质量。然而，NP目前没有接受有效的药物治疗。工程外泌体作为治疗疾病的药物输送系统具有很大的潜力。本研究通过片钳技术发现，n -甲基- d -天冬氨酸受体（NMDAR）亚基2A和2B的缺乏逆转了脊髓三叉神经尾核（SpVc）损伤后自发兴奋性突触后电流（sEPSC）频率和神经元兴奋性，而SpVc是NP的有效治疗靶点。因此，我们成功地使用了神经系统特异性狂犬病毒糖蛋白（RVG）肽修饰的外泌体（EXOs），该外泌体对N2a-Neuro细胞和SpVc组织具有良好的靶向能力。负载NR2A/B sirna的rvg - exo有效靶向SpVc神经元，进一步降低神经元兴奋性，缓解口面部NP。综上所述，我们的研究调查了NR2A/B在中枢伤害性致敏中的作用，并表明rvg - exos介导的靶向NR2A和NR2B的sirna递送对口腔面部NP治疗有效。观点：本研究探讨了NMDAR在神经损伤后SpVc中枢致敏中的重要作用。本研究创新性地探索了一种基于工程化rvg - exo的中央靶向给药系统，为口腔面部NP的靶向微创治疗提供基础。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Pain 医学-临床神经学

CiteScore

6.30

自引率

7.50%

发文量

441

审稿时长

42 days

期刊介绍： The Journal of Pain publishes original articles related to all aspects of pain, including clinical and basic research, patient care, education, and health policy. Articles selected for publication in the Journal are most commonly reports of original clinical research or reports of original basic research. In addition, invited critical reviews, including meta analyses of drugs for pain management, invited commentaries on reviews, and exceptional case studies are published in the Journal. The mission of the Journal is to improve the care of patients in pain by providing a forum for clinical researchers, basic scientists, clinicians, and other health professionals to publish original research.