Intranasal administration of angiotensin receptor shRNA to brain lowers blood pressure in spontaneously hypertensive rats

Neurogenic hypertension (NH) is characterized by heightened sympathetic activity mediated by angiotensin II in specific brain areas including the paraventricular nucleus and circumventricular organs. While strategies targeting sympathetic activity have shown effectiveness in managing NH, their invasive nature hinders their widespread clinical adoption. Conversely, nose-to-brain drug delivery is emerging as a promising approach to access the brain with reduced invasiveness. We hypothesize that the intranasal delivery of plasmid DNA encoding angiotensin receptor shRNA (PEAS) can effectively lower blood pressure (BP). PEAS was administered encapsulated within transferrin and Tetanus Toxin Fragment C-functionalized liposomes. Equal number of both male and female spontaneously hypertensive rats (SHR) were used to determine the effect of PEAS delivery to brain. Blood pressure was measured by the tail cuff measurement. Synthesized liposomes were found to be cationic, < 200 nm, entrapped over 88 % of the plasmid and protected PEAS from DNase degradation. In vitro, formulations caused a significant (p < 0.05) decrease (>70 %) in angiotensin receptor expression in brain endothelial cell lines, primary astrocytes and primary neurons. Intranasal administration of PEAS to SHR resulted in a significant (p < 0.05) reduction of angiotensin receptor gene expression in the brain. In the hypothalamus of SHR, intranasal administration resulted in > 70 % reduction in gene expression, ∼15 % greater than intravenous administration. Both routes were associated with an over 25 mmHg significant (p < 0.05) reduction in BP following administration of PEAS. Intranasal administration of PEAS effectively lowered BP in SHR, offering a promising non-invasive approach for managing NH.