Advancements in Protein-Based Therapeutic Delivery Approaches Targeting the Blood-Brain Barrier and Insights on Computational Strategies

Treating neurological disorders is challenging due to the blood-brain barrier (BBB), which limits therapeutic agents, including proteins and peptides, from entering the central nervous system. Despite their potential, the BBB's selective permeability is a significant obstacle. This review explores recent advancements in protein therapeutics for BBB-targeted delivery and highlights computational tools. Strategies such as nanoparticulate-mediated delivery, nose-to-brain delivery, lipid-based approaches, exosomes, cell-penetrating peptides (CPPs), and BBB shuttle peptides have been developed to overcome this barrier. Nanoparticulate systems deliver protein therapeutics across the BBB and can be surface-functionalized to target therapeutic agents into the brain parenchyma. Nose-to-brain delivery is a minimally invasive approach to bypass the BBB. Lipid-based strategies like liposomal systems and nanostructured lipid carriers enhance protein therapies by overcoming BBB restrictions. Exosomes, with unique lipid and surface protein compositions, and CPPs provide versatile drug delivery across the BBB. BBB shuttle peptides, designed for targeted brain delivery, show enhanced stability, efficiency, and cargo transport. Computational tools, notably molecular dynamics simulations, are essential in optimizing protein therapeutics for BBB penetration. These tools offer insights into molecular interactions, guiding the design and optimization of protein therapeutics for better brain penetration. Despite accuracy, limitations due to the BBB's complexity, integrating realistic models and experimental data can improve predictions.