The blood-brain barrier (BBB) is a highly selective gatekeeper. While providing essential protection against pathogens, BBB also poses a major challenge by restricting the delivery of systemically administered therapeutics. Consequently, there is a pressing need for innovative strategies that can efficiently and selectively target neuronal populations to treat diverse brain disorders. Nanomaterials enable transcellular transport across the endothelial layer; however, given the biomolecular corona paradigm, designing biomimetic hybrid nanoconstructs that preserve and leverage biological functionality within a complex physiological environment is more promising. Here, we investigated the potential of M13 bacteriophages as biocompatible and versatile nanovectors across the BBB. M13 phages exhibited: (i) a high cargo capacity within the main protein capsomer (here exploited for fluorescent labeling); (ii) offered genetic flexibility for ligand display; (iii) showed a natural propensity to efficiently cross the endothelial layer via specific intracellular pathways; (iv) maintained their structure and functionality intact. We also demonstrate that M13 phages engineered to target specific neuronal populations via single-domain antibody display retain their specificity after BBB translocation and in a protein- and cell-crowded environment. Overall, our results provide mechanistic insights emphasizing an unprecedented field of application for (engineered) M13 phages as biomimetic nanotools for targeting and delivery across the BBB.
Vercellino et al. (Fri,) studied this question.