Citation: Kai Wang, Yun Wang, Lihang Wang, Zhuhai Li, Xi Yu, Xuanhe You, Diwei Wu, Yueming Song, Jiancheng Zeng, Zongke Zhou, Shishu Huang, Yunfeng Lin. Therapeutic siRNA targeting CC chemokine receptor 2 loaded with tetrahedral framework nucleic acid alleviates neuropathic pain by regulating microglial polarization[J]. Chinese Chemical Letters, ;2025, 36(3): 109868. doi: 10.1016/j.cclet.2024.109868 shu

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

Kai Wang ^{a, 1} ,
Yun Wang ^{b, 1} ,
Lihang Wang ^a ,
Zhuhai Li ^a ,
Xi Yu ^a ,
Xuanhe You ^a ,
Diwei Wu ^a ,
Yueming Song ^a ,
Jiancheng Zeng ^a ,
Zongke Zhou ^a ,
Shishu Huang ^{a, *,} ,
Yunfeng Lin ^{b, c, d, *,}

a.
Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu 610041, China
b.
State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
c.
Sichuan Provincial Engineering Research Center of Oral Biomaterials, Chengdu 610041, China
d.
National Center for Translational Medicine, Shanghai Jiao Tong University, Shanghai 200240, China

h0794062@scu.edu.cn

yunfenglin@scu.edu.cn

Received Date: 17 February 2024
Revised Date: 1 April 2024
Accepted Date: 7 April 2024
Available Online: 8 April 2024

Figures(4)

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.
- Neuropathic pain,
- Tetrahedral framework nucleic,
- Small interfering RNA,
- Microglial polarization,
- Neuronal apoptosis
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