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Therapeutic siRNA targeting C-C chemokine receptor 2 loaded with tetrahedral framework nucleic acid alleviates neuropathic pain by regulating microglial polarization

神经病理性疼痛 趋化因子 核酸 趋化因子受体 受体 细胞生物学 化学 医学 材料科学 药理学 生物 生物化学
作者
Kai Wang,Yun Wang,Lihang Wang,Zhuhai Li,Xi Yu,Xuanhe You,Diwei Wu,Yueming Song,Jiancheng Zeng,Zongke Zhou,Shishu Huang,Yunfeng Lin
出处
期刊:Chinese Chemical Letters [Elsevier]
卷期号:: 109868-109868
标识
DOI:10.1016/j.cclet.2024.109868
摘要

Neuropathic pain (NP) is one of the most common pathological pain types and is associated with limited treatment options; moreover, it affects patients' quality of life and causes a heavy social burden. Despite the emphasis on inhibiting neuronal apoptosis to relieve NP, the crucial role of a neuroinflammation is often overlooked. Therefore, refocusing on the regulation of microglia polarization to create a more conducive environment for neuron holds great potential in NP treatment. In recent years, small interfering RNAs (siRNAs) had become an attractive therapeutic option. However, an efficient loading and delivery system for siRNA is still in lack. In our study, a nanostructured tetrahedral framework nucleic acid loaded with the small interfering RNA C-C chemokine receptor 2 (T-siCCR2) was successfully designed and synthesized for use in NP rat model in vivo and in a lipopolysaccharide (LPS)-induced inflammatory environment in vitro. This nanoscale complex is endowed with structural stability and satisfactory delivery efficiency while assuring the silencing effect of siRNA-CCR2. In vivo, T-siCCR2 treatment exhibited favorable effects on pain relief and functional improvement in the NP animal model by directly targeting microglia. In vitro, T-siCCR2 counteracts LPS-induced inflammation by inhibiting the differentiation of microglia toward the M1 phenotype, thus playing a neuroprotective role. RNA sequencing was subsequently performed to elucidate the underlying mechanism involved. These results indicate that T-siCCR2 may serve as a potential treatment option for NP in the future.
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