Thermoresponsive Gel for Sustained Nanoliposome-Mediated Nose-to-Brain Drug Delivery

Nose-to-brain drug delivery represents a promising non-invasive strategy for improving CNS targeting. However, conventional liquid formulations are limited by rapid mucociliary clearance and short mucosal residence time. This study developed a thermoresponsive in situ gel incorporating indocyanine green (ICG)-loaded nanoliposomes and evaluated its potential to enhance and modulate the ICG-associated brain distribution after intranasal administration of the formulation. ICG-loaded nanoliposomes were prepared using a modified thin-film hydration method and incorporated into a poloxamer-based gel containing hyaluronic acid and Carbomer 940 as mucoadhesive components. The nanoliposomes exhibited a mean particle size of 124 ± 3.25 nm, a unimodal size distribution, and a high ICG encapsulation efficiency of 93.33%. Rheological analysis confirmed a temperature-triggered sol-to-gel transition at the physiological nasal temperature (~32 °C), shear-thinning behavior, and rapid structural recovery suitable for intranasal application. Ex vivo fluorescence imaging in rats demonstrated distinct biodistribution profiles for the ICG-associated signal delivered via the liquid nanoliposomes and gel-incorporated nanoliposomes. Although the liquid liposomes showed faster early signal at 4 h, the gel formulation produced stronger and more sustained brain fluorescence at later time points. At 8 h and 24 h, whole-brain fluorescence was approximately twofold higher with the gel formulation than with the liquid liposomes formulation. These findings indicate that this thermoresponsive gel enhances nasal retention and may modulate the delivery profile of the nose-to-brain transport, supporting its potential as a platform for CNS-targeted delivery and the development of more effective therapies for neurodegenerative diseases.