Engineering EVs-Mediated mRNA Delivery Regulates Microglia Function and Alleviates Depressive-Like Behaviors

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.