Thermosensitive hydrogel designed for improving the antidepressant activities of genipin via intranasal delivery

[Display omitted] •Hydrogel has a good thermosensitive property.•Hydrogel presents good genipin release behavior.•Hydrogel exerts significant antidepressant effects. The release of drugs in the brain is a challenge due to the blood–brain barrier, but intranasal administration of hydrogels enables the continuous release and quick targeting of drugs into the brain. The aim of this study was to prepare a genipin/hydroxypropyl-β-cyclodextrin inclusion complex thermosensitive hydrogel system (genipin-THS) and evaluate its antidepressant effects. The genipin-THS was constructed using the cold method and was further optimized based on the results of gelation temperature and in vitro drug release. In the in vivo experiment, the genipin-THS significantly reduced the immobility time of mice displaying behavioral despair, decreased the ptosis score and increased the change in the body temperature of mice induced by reserpine, and improved abnormal levels of neurotransmitters (including 5-hydroxytryptamine and norepinephrine) in brain. In addition, the intranasally administered genipin-THS increased the bioavailability of the drug in the hippocampus, and the fluorescence distribution also showed that the thermosensitive hydrogel continuously released the drug for a longer time. In summary, the intranasally administered genipin-THS improved the bioavailability of genipin in the brain, increased its brain targeting, and further enhanced its antidepressant effects on depressive disorder.