Staff member

Targeting the transferrin receptor (TfR) holds promise for drug delivery across the blood-brain barrier (BBB), but conventional strategies suffer from competition with endogenous ligands and suboptimal trafficking. To overcome these limitations, we engineered a library of T7 peptide-functionalised pH-responsive polymersomes with precise control over ligand density and ligand insertion depth (delta) within a poly(ethylene glycol) (PEG) corona. We generated nanoparticles with delta values ranging from 0.3 (deeply inserted ligands) to 1.0 (fully exposed ligands), enabling systematic evaluation of how spatial ligand presentation influences BBB interactions. In vitro studies revealed that delta = 1.0 polymersomes exhibited efficient transcytosis, whereas delta = 0.6 polymersomes promoted endothelial retention, a divergence likely linked to differential receptor clustering and trafficking kinetics. Notably, TfR-mediated transport occurred independently of PACSIN2, distinguishing it from tubular transcytosis pathways observed with LRP1-targeted systems. These findings establish avidity-by-design as a strategy to tailor nanocarriers for either BBB penetration or vascular targeting, offering a modular platform for neurological therapeutics.

JTD Keywords: Brain endothelium, Multivalency, Pacsin2, Ph, Ph-sensitive polymersome, Transcytosis, Transferrin, Transferrin receptor

Efficient drug delivery across the blood–brain barrier (BBB) remains a significant obstacle in treating central nervous system (CNS) disorders. This review provides an in-depth analysis of the structural and molecular mechanisms underlying BBB integrity and its functional properties. We detail the role of key cellular and molecular components that regulate selective molecular transport across the barrier, alongside a description of the current therapeutic approaches for brain drug delivery, including those leveraging receptor-mediated transcytosis. Emphasis is placed on multivalency-based strategies that enhance the specificity of nanoparticle targeting and improve transport efficacy across the BBB. Additionally, we discuss the added value of integrating mathematical and computational models with experimental validation for accelerating BBB-targeted delivery systems optimisation.

JTD