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RVG engineered extracellular vesicles-transmitted miR-137 improves autism by modulating glucose metabolism and neuroinflammation

Molecular Psychiatry (2025)Cite this article

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Abstract

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder. The microglia activation is a hallmark of ASD, which involves increased glycolysis. Elevated glycolysis regardless of oxygen availability, known as “Warburg effect”, is crucial to pathogenesis in neuropsychiatric disorders. Psychiatric risk gene MIR137 plays an important role in neurogenesis and neuronal maturation, but the impact on neuroinflammation and glucose metabolism remains obscure. Extracellular vesicles (EVs) can delivery miR-137 crossing the blood-brain barrier. Meanwhile, EVs can help miR-137 avoid being rapidly degraded by endogenous nucleases. Here, after first detecting miR-137 decreased both in the peripheral blood of individuals with ASD and the serum and cerebellum of BTBR mice, we demonstrated that microglia activation, the level of lactate and key enzymes (HK2, PKM2 and LDHA) involved in glycolysis were increased significantly in BTBR mice. Of particular note, EVs engineered by rabies virus glycoprotein (RVG) could promote the miR-137 (RVG-miR137-EVs) targeted to the brain accurately, and alleviated autism-like behaviors. Pro-inflammatory activation of BTBR mice was considerably inhibited by RVG-miR137-EVs via tail vein administration, accompanied by decreased lactate production. Mechanically, these effects were attributed to TLR4, the key target gene, which was regulated by miR-137. The TLR4/NF-κB pathway was inhibited, subsequently reducing HIF-1α and repressing the transcription of HK2, PKM2 and LDHA involved in glycolysis. Pharmacological inhibition of glycolysis and TLR4 attenuated microglial activation and lactate production, ultimately improved autism-like behaviors of BTBR mice. In conclusion, our results indicated that miR-137 could alleviate autism-like behaviors by HIF-1α-mediated adaptive metabolic changes in glycolysis and neuroinflammation.

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Fig. 1: Preparation and characterization of engineered RVG-miR137-EVs.
Fig. 2: Engineered RVG-EVs efficiently deliver miR-137 into the brain and attenuate autism-like behaviors in BTBR mice.
Fig. 3: RVG-EVs mediated delivery of miR-137 regulates TLR4/NF-κB pathway to attenuate neuroinflammation.
Fig. 4: RVG-miR137-EVs reduce elevated glycolysis in the cerebellum of BTBR mice and microglia.
Fig. 5: RVG-miR137-EVs regulate neuroinflammation and glycolysis by interacting with TLR4 in BTBR mice and microglia.
Fig. 6: miR-137 regulates neuroinflammation and glycolysis by interacting with TLR4 in microglia.

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Acknowledgements

We sincerely thank the assistance provided from Province Key Laboratory of Children development and genetic research (Harbin Medical University, Heilongjiang, China) and Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Ministry of Education (Harbin Medical University, Heilongjiang, China).

Funding

This study was supported by grants from the National Natural Science Foundation of China (81973068); the Open Project Program of Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (LPHGRDC2021-004); Postgraduate Research & Practice Innovation Program of Harbin Medical University (YJSCX2023-19HYD); the Excellent Young Teachers’ Basic Research Support Program of Heilongjiang Province (YQJH2023040); Heilongjiang Province Postdoctoral Start-up Fund (LBH-Q19029).

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  1. Department of Children’s and Adolescent Health, Public Health College, Harbin Medical University, Harbin, 150081, China

    Qian Qin, Mengyue Li, Linlin Fan, Xin Zeng, Danyang Zheng, Han Wang, Yutong Jiang, Xinrui Ma, Lei Xing, Lijie Wu & Shuang Liang

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  1. Qian Qin
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Contributions

QQ, SL and LJW conceptualized and designed experiments for this research. QQ performed molecular experiments; analyzed the data; and wrote and edited the original manuscript. QQ and LLF preprocessed and analyzed the molecular experiments. MYL, LLF and XZ performed bioinformatic analysis. LX and XRM performed cell culture experiments. DYZ, HW and YTJ performed mice breeding and mice behavior experiments. SL obtained funding. SL and LJW critically reviewed the manuscript. All authors read and approved the final version of the manuscript.

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Correspondence to Lijie Wu or Shuang Liang.

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All animal studies and experimental procedures were approved by the Ethics Committee of Harbin Medical University (HMUIRB20210002) and were performed according to the guidelines of the Institutional Animal Care and Use Committee of the university. Additionally, the number of mice used in the experiments was minimized as much as possible in accordance with the 3R-principle (replacement, reduction, and refinement). We carried out euthanasia according to regulations for all mice that reached the end of their lives.

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Qin, Q., Li, M., Fan, L. et al. RVG engineered extracellular vesicles-transmitted miR-137 improves autism by modulating glucose metabolism and neuroinflammation. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-02988-0

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