Crossing the blood-brain barrier: advances in dendrimer-based nanocarriers for central nervous system delivery

Dendrimer-based nanocarriers are emerging as transformative platforms to overcome the challenge of crossing the blood-brain barrier (BBB) in the treatment and diagnosis of central nervous system (CNS) disorders. Their highly branched, monodisperse architecture enables precise control over size, surface chemistry, and cargo loading, distinguishing them from conventional nanocarriers such as liposomes and polymeric nanoparticles. This review summarizes recent advances in designing dendrimers for targeted brain delivery across diverse neurological conditions. In particular, advances in dendrimer synthesis and functionalization including PEGylation, ligand conjugation, and biomimetic coatings have significantly improved BBB permeability, biocompatibility, and disease-specific targeting. Key dendrimer classes, including PAMAM, PPI, phosphorus, and peptide-based variants, exploit multiple BBB crossing mechanisms such as adsorptive-mediated, receptor- and carrier-mediated transcytosis. We then focus on therapeutic applications and clinical translation, highlighting candidates such as OP-101 and ¹⁸F-OP-801, which demonstrate targeted delivery and imaging capabilities in neuroinflammatory and oncological models. Despite these advances, challenges remain in addressing dendrimer-associated toxicity, scalable manufacturing, and the heterogeneity of BBB dysfunction across disease states. Looking ahead, integrating artificial intelligence (AI) for BBB permeability prediction and the adoption of advanced biomimetic and aptamer-based targeting strategies could accelerate the development of next-generation dendrimer therapeutics.