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