Nasal-to-brain siRNA delivery based on trace amine associated receptor for improving cognitive function

Area of Science:

• Neuroscience
• Nanotechnology
• Gene Therapy

Background:

• Central nervous system (CNS) disorders require effective drug delivery across the blood-brain barrier (BBB).
• Nasal-to-brain delivery offers a promising alternative to bypass the BBB for targeted CNS treatment.
• Radiation-induced brain injury (RBI) presents a significant challenge in CNS therapeutics.

Purpose of the Study:

• To develop a novel nasal-to-brain delivery system for small interfering RNA (siRNA) to treat radiation-induced brain injury (RBI).
• To engineer spermidine-modified ginseng-derived extracellular vesicles (S-GEVs) nanoparticles (S-GEVs@siRNA) for enhanced siRNA delivery targeting Alox12B.

Main Methods:

• RNA sequencing identified the p53 signaling pathway and Alox12B upregulation in RBI mice.
• Spermidine modification of ginseng-derived extracellular vesicles (GEVs) enhanced targeting of olfactory receptor-trace amine associated receptor (TAAR).
• Intranasal administration of S-GEVs@siRNA facilitated uptake by olfactory receptor neurons (ORNs) and subsequent brain entry.

Main Results:

• S-GEVs@siRNA nanoparticles were efficiently internalized by ORNs via the olfactory nerve pathway and entered the brain.
• The nanoparticles successfully downregulated Alox12B expression, reducing p53-mediated neuronal ferroptosis.
• Treatment significantly improved synaptic function and alleviated cognitive dysfunction in RBI models.

Conclusions:

• S-GEVs@siRNA nanoparticles provide an effective nasal-to-brain delivery strategy for CNS disorders.
• This system demonstrates neuroprotective effects and alleviates cognitive deficits associated with RBI.
• The developed nanoparticles hold potential for treating various CNS diseases via targeted gene therapy.