2. Academic Validation
  3. Targeted neural stem cell-derived extracellular vesicles loaded with Sinomenine alleviate diabetic peripheral neuropathy via WNT5a/TRPV1 pathway modulation

Targeted neural stem cell-derived extracellular vesicles loaded with Sinomenine alleviate diabetic peripheral neuropathy via WNT5a/TRPV1 pathway modulation

  • J Nanobiotechnology. 2025 Aug 26;23(1):588. doi: 10.1186/s12951-025-03678-3.
Ji Chen # 1 2,  Lin Zhu # 3,  Yangyuxi Chen 4,  Yuan Liu 5,  Wen Chen 5,  Xinxin Liu 6,  Fengrui Yang 7 8
Affiliations

Affiliations

  • 1 Department of Endocrinology, Yuebei People's Hospital, Shantou University Medical College, No. 133, South Huimin Road, Shaoguan, 512026, Guangdong Province, P. R. China.
  • 2 Department of Endocrinology, Hunan University of Medicine General Hospital, No. 144, South Jinxi Road, Huaihua, 418000, Hunan Province, P. R. China.
  • 3 Department of Anesthesiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, No. 69 West Chuanshan Road, Hengyang, 421001, Hunan Province, P. R. China.
  • 4 Yali High School International Department, No. 428 West Laodong Road, Changsha, 410007, Hunan, P.R. China.
  • 5 Department of Anesthesiology, Yuebei People's Hospital, Shantou University Medical College, No. 133, South Huimin Road, Shaoguan, 512026, Guangdong Province, P. R. China.
  • 6 Department of Anesthesiology, Hunan University of Medicine General Hospital, No. 144, South Jinxi Road, Huaihua, 418000, Hunan Province, P. R. China.
  • 7 Department of Anesthesiology, Yuebei People's Hospital, Shantou University Medical College, No. 133, South Huimin Road, Shaoguan, 512026, Guangdong Province, P. R. China. 332530935@qq.com.
  • 8 Department of Anesthesiology, Hunan University of Medicine General Hospital, No. 144, South Jinxi Road, Huaihua, 418000, Hunan Province, P. R. China. 332530935@qq.com.
  • # Contributed equally.
PMID: 40855286 DOI: 10.1186/s12951-025-03678-3
Abstract

Background: Diabetic peripheral neuropathy (DPN) is one of the most prevalent and debilitating complications of diabetes, marked by chronic neuroinflammation, immune dysregulation, and progressive neuronal degeneration. Current treatments offer limited efficacy, largely focusing on symptomatic relief rather than addressing the underlying disease mechanisms. There is a critical need for disease-modifying therapies that target the molecular basis of DPN.

Results: In this study, we developed a novel targeted nanotherapeutic system-ZH-1c-EVs@SIN-composed of neural stem cell-derived extracellular vesicles (NSC-EVs) modified with the ZH-1c aptamer and loaded with the anti-inflammatory compound sinomenine (SIN). This system was specifically designed to target microglia and inhibit the WNT5a/TRPV1 signaling pathway. Transcriptomic profiling of microglia revealed key gene networks implicated in DPN pathology and responsive to SIN treatment. Functional assays demonstrated that ZH-1c-EVs@SIN facilitated a shift in microglial phenotype from pro-inflammatory M1 to anti-inflammatory M2, significantly reduced inflammatory cytokine expression, and restored levels of neuronal regulatory proteins. Nanoparticle tracking analysis and transmission electron microscopy confirmed optimal vesicle size and morphology, while fluorescence imaging showed efficient uptake by microglia. In vivo studies in a murine model of DPN revealed marked improvements in pain-related behavior and histopathological signs of nerve damage.

Conclusion: ZH-1c-EVs@SIN represents a promising therapeutic strategy for DPN, offering targeted immunomodulation and enhanced neural repair via regulation of the WNT5a/TRPV1 signaling axis. This nano-delivery platform introduces a novel and precise approach to intervening in diabetic neuropathy and may be applicable to Other neuroinflammatory conditions.

Keywords

Aptamer modification; Diabetic peripheral neuropathy; Immune-Inflammatory homeostasis; Microglial polarization; Neural stem Cell-Derived extracellular vesicles; Sinomenine; WNT5a/TRPV1 pathway.

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