Intranasal delivery of peptide-modified quercetin liposomes suppresses neuroinflammation.

Neuroinflammation, a central pathological mechanism in central nervous system disorders, remains challenging to treat due to the restrictive nature of the blood-brain barrier and poor drug delivery efficiency. In this study, we developed a novel intranasal brain-targeted delivery system by constructing peptide-modified quercetin liposomes (QuR-lipo). By using intranasal administration to bypass the blood-brain barrier, QuR-lipo demonstrated higher uptake and accumulation in the brain compared to unmodified liposomes. This system disrupts the vicious cycle between neuroinflammation and oxidative stress, thereby improving neurobehavioral outcomes. QuR-lipo displayed a uniform particle size distribution, high encapsulation efficiency, and sustained-release characteristics. In vitro studies showed that QuR-lipo enhanced intracellular drug accumulation by modulating endocytic pathways, effectively inhibited aberrant microglial activation, suppressed pro-inflammatory cytokine cascades, and scavenged reactive oxygen species. In a lipopolysaccharide-induced neuroinflammation animal model, intranasal delivery of QuR-lipo significantly increased brain drug concentration, improved spatial memory deficits and depression-like behaviors, and suppressed microglial activation. Mechanistic studies revealed that QuR-lipo reversed neurological dysfunction by inhibiting the inflammasome signaling axis. Together, these findings provide an innovative strategy for brain-targeted delivery of natural bioactive compounds to treat neurodegenerative diseases.