The PSD-95 inhibitor NA-1 is delivered to the brain upon nasal administration with uptake into the olfactory bulb improved by co-administration with the cell-penetrating peptides lowPro and Tat

Ischemic stroke affects millions of people annually with limited treatment options targeting excitotoxicity, a major cause of cognitive impairment. The PSD-95 inhibitor NA-1 has demonstrated neuroprotective potential, but its efficacy via intravenous administration is hindered by broad systemic distribution, reduced brain exposure, and interaction with thrombolytic agents like alteplase. This study explores the potential of nasal administration as an alternative delivery route to enhance brain uptake and reduce systemic off-target effects of NA-1. A porcine primary olfactory model was exploited to evaluate NA-1 permeability and the impact of co-administration with the cell-penetrating peptides Tat, LowPro, and PenShuf. NA-1 alone permeated the model to a greater extent than a similar sized model dextran compound, with PenShuf improving NA-1 permeability but compromising barrier integrity in vitro. In vivo, nasal administration to mice achieved brain uptake of NA-1, particularly in the olfactory bulb, with co-administration of Tat and LowPro enhancing olfactory bulb delivery. Compared to intravenously administered NA-1, nasal delivery resulted in significantly lower off-target tissue distribution. These findings highlight nasal administration as a qualified alternative for NA-1 delivery, with potential to bypass the limitations of intravenous administration and enable concurrent use with alteplase during acute ischemic stroke.