The Avidity Paradox: Optimising T7-Polymersome Valency for Enhanced Blood-Brain Barrier Transcytosis

Ana Alves – Postdoctoral Researcher, Universidade do Porto; Peter Pfeifer – Research Technician, Institute for Bioengineering of Catalonia (IBEC); Giuseppe Battaglia – ICREA Professor, Institute for Bioengineering of Catalonia (IBEC); Cátia Lopes – Postdoctoral Researcher, Institute for Bioengineering of Catalonia (IBEC)

Introduction: Over 98% of small-molecule drugs fail to cross the blood-brain barrier (BBB), leaving cancers like glioblastoma (GBM) largely untreatable. While the transferrin receptor (TfR) is a known target for BBB crossing, it is also highly overexpressed in GBM cells. This study explores poly(ethylene glycol)-b-poly(lactic acid) (PEG-b-PLA) polymersomes functionalised with the T7 peptide (His-Ala-Ile-Tyr-Pro-Arg-His) as a dual-targeting modality to deliver chemotherapeutic drugs to GBM. T7 targets the TfR without competing with endogenous transferrin, leveraging receptor-mediated transcytosis to bypass the BBB efficiently.