Targeting glial cells in the brain constitutes a formidable challenge due to the presence of the blood-brain barrier (BBB) and the difficulty in achieving specific targeting. Intranasal (IN) administration offers a promising solution to bypass the BBB for delivery directly to the brain, while nanotechnology-based delivery provides tailored targeting capabilities. Here, we report dendrimer-based nanosystems developed for IN administration to target astrocytes and microglia, two types of glial cells that play important roles in maintaining brain homeostasis. Specifically, we demonstrate that bola-amphiphilic glycodendrimers, Ia and Ib, which bear glucose and mannose terminals, respectively, target astrocytes and microglia in the mouse brain. These two glycodendrimers, composed of a hydrophobic bola-lipid in the middle connected with two hydrophilic poly(amidoamine) dendrons, were effectively synthesized via a click reaction using unprotected carbohydrate building units, and self-assembled into small and spherical nanoparticles by virtue of their amphiphilicity. In a mouse model, both dendrimer nanoparticles successfully reached the brain following IN administration, where the glucose-dendrimer Ia selectively targeted astrocytes and the mannose-dendrimer Ib targeted microglia. These findings highlight the potential of glycodendrimer-based nanosystems for precise targeting in the brain and offer a promising perspective for treating central nervous system (CNS) diseases.
