Binary Nano-inhalant Formulation of Icariin Enhances Cognitive Function in Vascular Dementia via BDNF/TrkB Signaling and Anti-inflammatory Effects.

Vascular dementia (VaD) has a serious impact on the patients' quality of life. Icariin (Ica) possesses neuroprotective potential for treating VaD, yet its oral bioavailability and blood-brain barrier (BBB) permeability remain challenges. This research introduced a PEG-PLGA-loaded chitosan hydrogel-based binary formulation tailored for intranasal delivery, enhancing the intracerebral delivery efficacy of neuroprotective agents. The formulation underwent optimization to facilitate BBB crossing, with examinations conducted on its particle size, morphology, drug-loading capacity, in vitro release, and biodistribution. Using the bilateral common carotid artery occlusion (BCCAO) rat model, the therapeutic efficacy of this binary formulation was assessed against chitosan hydrogel and PEG-PLGA nanoparticles loaded with Ica. Post-intranasal administration, enhanced cognitive function was evident in chronic cerebral hypoperfusion (CCH) rats. Further mechanistic evaluations, utilizing immunohistochemistry (IHC), RT-PCR, and ELISA, revealed augmented transcription of synaptic plasticity-associated proteins like SYP and PSD-95, and a marked reduction in hippocampal inflammatory markers such as IL-1β and TNF-α, highlighting the formulation's promise in alleviating cognitive impairment. The brain-derived neurotrophic factor (BDNF)/tropomyosin related kinase B (TrkB) pathway was activated significantly in the binary formulation compared with the other two. Our study demonstrates that the intranasal application of chitosan hydrogel loaded with Ica-encapsulated PEG-PLGA could effectively deliver Ica into the brain and enhance its neuroprotective effect.