Sometimes less is more: avidity-dependent transport of targeted polymersomes across the blood–brain-barrier†

Over the past decade, roughly 10% of new FDA-approved drugs targeted central nervous system (CNS) disorders, while it has been estimated that 98% of small-molecule drugs and nearly all large-molecule therapeutics are unable to cross the blood–brain barrier (BBB). There is a clear need for novel therapeutic modalities that promote receptor-mediated transcytosis modulation and efficiently deliver drugs to the brain. Here, we show that poly(ethylene glycol)-b-poly(lactic acid) (PEG-b-PLA) polymersomes functionalised with a transferrin receptor (TfR)-targeted peptide can effectively deliver a glioblastoma small drug therapeutic (3,6-bis(2,3,4,6-tetra-O-acetyl-β-glucopyranosyl)xanthone; XGAc) through a two-dimensional model of the BBB and that the transport is dependent on the avidity of the nanoformulation. By adjusting the density of targeting peptides on polymersomes, we present a novel strategy to enhance the efficiency of BBB receptor-mediated transcytosis. These findings highlight the promise of precision-tuned polymersomes in overcoming the BBB and advancing treatments for glioblastoma and other brain diseases.