A LIFU-responsive phase-change nanoplatform enhances hippocampal galantamine exposure and cognitive outcomes in APP/PS1 mice

Alzheimer’s disease (AD) lacks spatiotemporally controllable strategies for drug delivery to deep brain targets. Galantamine (GTM) is clinically used for symptomatic management of AD, yet systemic dosing is constrained by peripheral adverse effects and limited, nonselective brain exposure. Here, we engineered a PEGylated phase-change liposomal nanoplatform co-loading GTM and perfluoropentane (PFP) (PEG-LIP@PFP@GTM) to integrate noninvasive nose-to-brain delivery with low-intensity focused ultrasound (LIFU)-assisted enhancement of GTM exposure in the hippocampal region. PEG-LIP@PFP@GTM showed a hydrodynamic diameter of 158.8 ± 1.6 nm with a PDI of 0.165 ± 0.017, an encapsulation efficiency of 69.26 ± 2.07%, and a drug loading content of 6.37 ± 0.65%. PFP endowed the formulation with thermo-responsive phase-transition behavior and LIFU-enhanced GTM release under physiological-temperature conditions. In vivo fluorescence imaging and ex vivo brain sectioning provided evidence of brain accessibility after intranasal administration, while also identifying 4 h post-dosing as a practical window for hippocampal LIFU irradiation. In APP/PS1 mice, compared with the non-irradiated nanoplatform group, phase-change liposomes combined with hippocampal LIFU irradiation significantly increased PSD95 fluorescence intensity (p = 0.0028) and improved Y-maze novel-arm time (p = 0.0003) and Morris water maze target-quadrant time (p = 0.0237), and significantly reduced the Aβ-positive area (p = 0.0461). Histological examination revealed no overt abnormalities in the nasal mucosa or major peripheral organs under the tested conditions. Collectively, these findings support combining intranasal nanocarrier delivery with externally applied hippocampal LIFU, with LIFU activation providing additional benefit beyond non-irradiated nanocarrier treatment under the tested conditions.