How can targeted protein functionalisation improve transport of RNA therapeutics across the BBB for treating neurodegenerative diseases?

Neurodegenerative diseases remain among the leading causes of disability worldwide, yet effective disease-modifying therapies capable of slowing or halting disease progression remain largely unavailable. RNA therapeutics have emerged as a promising disease-modifying modality through their ability to selectively target the molecular mechanisms underlying neurodegeneration; however, their clinical application is severely constrained by the blood–brain barrier (BBB), which restricts efficient delivery to the central nervous system. Consequently, considerable effort has been directed towards developing delivery platforms capable of overcoming this barrier. Among these, protein functionalisation of nanoparticles has emerged as a particularly promising approach by enabling receptor-mediated or adsorptive transport across the BBB. This review critically evaluates current protein functionalisation strategies for BBB-targeted RNA delivery, comparing endogenous receptor-targeting ligands, engineered targeting peptides, receptor-independent approaches, and covalent versus non-covalent conjugation methods using a mechanistic framework encompassing targeting, intracellular trafficking, transcytosis, and therapeutic delivery. Comparative analysis indicates that lactoferrin currently represents the strongest evidence-supported targeting ligand owing to its comprehensive mechanistic validation and consistently superior quantitative delivery, whereas rabies virus glycoprotein-derived peptides demonstrate the greatest targeting specificity and long-term potential through neuron-selective delivery. Covalent conjugation emerged as the preferred functionalisation strategy by providing superior control over ligand stability, orientation, and surface architecture, enabling more predictable BBB transport than non-covalent approaches. However, clinical translation remains limited by heterogeneous preclinical methodologies, incomplete understanding of intracellular trafficking, and manufacturing challenges. Establishing standardised evaluation frameworks, advancing mechanistic characterisation, and developing rationally engineered multifunctional nanocarriers will be essential for enabling the clinical translation of BBB-targeted RNA therapeutics.