Related Experiment Video
Updated: Jun 1, 2025
Harnessing the Power of MicroRNA Cargoes in Small Extracellular Vesicles Released from Fresh-Frozen Human Brain Sections
Published on: November 8, 2024
Engineering EVs-Mediated mRNA Delivery Regulates Microglia Function and Alleviates Depressive-Like Behaviors
Kezhen Ge1,2, Zetai Bai2, Jiwei Wang1
1Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Jiangsu, 210009, P. R. China.
Abstract:
The development of new non-neurotransmitter drugs is an important supplement to the clinical treatment of major depressive disorder. The latest development of mRNA therapy provides the possibility for the treatment of some major diseases. The endoplasmic reticulum (ER) and mitochondria constitute a highly interconnected set of fundamental organelles within cells. The interconnection between them forms specific microdomains that play pivotal roles in calcium signaling, mitochondrial dynamics, inflammation, and autophagy. Perturbations in ER-mitochondrial connections may contribute to the progression of neurological disorders and other diseases. Herein, an extracellular vesicles-based delivery system, grounded in mRNA gene therapy and integrated with nanomedicine technology is devised. This system is engineered to traverse the blood-brain barrier and specifically target the central nervous system (CNS), facilitating the simultaneous delivery of mRNA drugs and metallic nanozymes into the brain. This dual-pronged approach, targeting ER and mitochondrial crosstalk, inhibits microglial overactivation, promotes M2 polarization of microglia, and suppresses the NF-κB signaling pathway. Consequently, it significantly alleviates Lipopolysaccharides-induced neuroinflammatory responses and ameliorates anxiety- and depression-like behaviors. This study demonstrates a novel antidepressant therapeutic strategy and establishes a new paradigm for mRNA gene therapy in CNS diseases.
Insights
This study introduces a novel mRNA therapy using extracellular vesicles to treat depression by targeting brain cell communication. The approach reduces neuroinflammation and anxiety-like behaviors, offering a new therapeutic strategy for central nervous system diseases.
Area of Science:
- Neuroscience
- Cell Biology
- Pharmacology
Background:
- Major depressive disorder treatment is supplemented by non-neurotransmitter drugs.
- Endoplasmic reticulum (ER) and mitochondria crosstalk is crucial for cellular functions and implicated in neurological disorders.
- Messenger RNA (mRNA) therapy offers potential for treating complex diseases.
Purpose of the Study:
- To develop an extracellular vesicle-based mRNA delivery system for targeting the central nervous system (CNS).
- To investigate the therapeutic potential of targeting ER-mitochondrial crosstalk for neuroinflammation and depression.
Main Methods:
- Engineered extracellular vesicles to deliver mRNA drugs and nanozymes across the blood-brain barrier.
- Targeted ER-mitochondrial pathways to modulate microglial activation and inflammatory signaling.
- Assessed neuroinflammatory responses and anxiety- and depression-like behaviors in a rodent model.
Main Results:
- The system successfully delivered mRNA and nanozymes to the CNS.
- Targeting ER-mitochondrial crosstalk inhibited microglial overactivation and suppressed the NF-κB pathway.
- Neuroinflammation was significantly reduced, and depression-like behaviors were ameliorated.
Conclusions:
- This study presents a novel therapeutic strategy for depression using mRNA gene therapy and nanomedicine.
- The developed system establishes a new paradigm for treating CNS diseases by modulating organelle crosstalk.
- Extracellular vesicle-mediated mRNA delivery shows promise for treating neuroinflammatory disorders.
