Drop to Gate Nasal Drops Attenuates Sepsis-Induced Cognitive Dysfunction.

Area of Science:

• Biomedical Engineering
• Neuroscience
• Pharmacology

Background:

• Nasal drug delivery offers a non-invasive route to the central nervous system (CNS), bypassing the blood-brain barrier.
• Developing effective strategies to enhance drug concentration and residence time in the nasal cavity is crucial for CNS disease treatment.
• Sepsis-induced cognitive dysfunction involves neuroinflammation mediated by microglia.

Purpose of the Study:

• To design and evaluate a novel Drop to Gate nasal drop (DGND) system for efficient brain drug delivery.
• To investigate the potential of DGND in treating sepsis-induced cognitive dysfunction by targeting neuroinflammation.
• To enhance drug delivery to the brain via nasal administration, improving therapeutic outcomes for CNS disorders.

Main Methods:

• Development of a thermogel-based DGND system incorporating C8-GelMA and SRT1720 (SA) nanogel.
• Utilizing hydrophobic interactions and UV cross-linking to form drug-loaded nanogels responsive to matrix metalloproteinases (MMPs).
• In vitro assessment of DGND's anti-inflammatory effects on lipopolysaccharide (LPS)-induced BV2 cells and in vivo evaluation in a mouse model of sepsis-induced cognitive dysfunction.

Main Results:

• The DGND system successfully formed an in situ gel in the nasal cavity, increasing drug residence time and delivery efficiency.
• In vitro studies showed DGND effectively alleviated LPS-induced BV2 inflammation.
• In vivo studies demonstrated that DGND targeted the nasal mucosa, delivered drugs to the brain, activated Sirt1, reduced microglial inflammation, and improved cognitive deficits in sepsis mice.

Conclusions:

• The DGND system provides an efficient and non-invasive strategy for delivering drugs to the brain via nasal administration.
• DGND shows significant potential for treating CNS diseases, particularly sepsis-induced cognitive dysfunction, by modulating neuroinflammation.
• The developed thermogel-based nanocarrier system offers a promising platform for enhanced brain drug delivery and therapeutic intervention.