Dual Ligand Cooperation at the Plasma Membrane Drives Transport of Engineered Small Extracellular Vesicles Across Brain Endothelial Cells

Our stroke medical 'professionals' can explain how this can be used to get new neurons moved to the right places via neurogenesis. At least if they have more than two functioning neurons to rub together.

 This snippet from the email blast is great for us:
The efficacy of these strategies has been supported by therapeutic outcomes in
preclinical models of stroke, Alzheimer’s and Parkinson’s disease… 
Dual Ligand Cooperation at the Plasma Membrane Drives Transport of Engineered Small Extracellular Vesicles Across Brain Endothelial Cells

Inês Albino†,‡, Elena Ambrosetti§,, Ana Teixeira§, Paula Sampaio⊥,, Miguel M. Lino*,†,‡, & Lino Ferreira*,†,‡ 

 † Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal. 

 ‡ IIIUC-Institute of Interdisciplinary Research, University of Coimbra, Coimbra, Portugal. 

  Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal. 

 § Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. 

 ⊥ Institute for Research and Innovation in Health (I3S), University of Porto, Porto, Portugal. 

  Institute for Molecular and Cellular Biology (IBMC), University of Porto, Porto, Portugal. 

ABSTRACT The copyright holder for this preprint bioRxiv preprint doi: https://doi.org/10.64898/2026.01.21.700773 ; this version posted January 23, 2026. (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The natural delivery properties of small ABSTRACT The copyright holder for this preprint bioRxiv preprint doi: https://doi.org/10.64898/2026.01.21.700773 ; this version posted January 23, 2026. (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The natural delivery properties of small extracellular vesicles (sEVs) can be harnessed and enhanced through engineering to create a new class of biotherapeutics, particularly for central nervous system (CNS) disorders. While evidence supports the ability of sEVs to cross biological barriers and deliver functional cargo to target cells, a limited understanding of their uptake and transport across the brain hinders their translational potential. In this study, we investigated either native and engineered sEVs, developed by us, using a novel modular engineering platform that employs a dual-targeting strategy to facilitate uptake and transport through human brain endothelial cells (BECs). By utilizing super-resolution microscopy, we provided direct insights into the mechanisms of docking, intracellular sorting, and transport of engineered sEVs. The engineered sEVs formulation demonstrated significantly enhanced uptake, intracellular trafficking across BECs, and the ability to bypass degradative pathways. In vivo, the engineered sEVs exhibited preferential accumulation in the brain choroid plexus, a structure located within the lateral and fourth ventricles, thereby effectively targeting the blood-cerebrospinal fluid (CSF) barrier. These findings highlight the potential of combining advanced targeting strategies with high-resolution imaging to study sEV interactions with the brain biological barriers and develop more effective CNS therapies. vesicles (sEVs) can be harnessed and enhanced through engineering to create a new class of biotherapeutics, particularly for central nervous system (CNS) disorders. While evidence supports the ability of sEVs to cross biological barriers and deliver functional cargo to target cells, a limited understanding of their uptake and transport across the brain hinders their translational potential. In this study, we investigated either native and engineered sEVs, developed by us, using a novel modular engineering platform that employs a dual-targeting strategy to facilitate uptake and transport through human brain endothelial cells (BECs). By utilizing super-resolution microscopy, we provided direct insights into the mechanisms of docking, intracellular sorting, and transport of engineered sEVs. The engineered sEVs formulation demonstrated significantly enhanced uptake, intracellular trafficking across BECs, and the ability to bypass degradative pathways. In vivo, the engineered sEVs exhibited preferential accumulation in the brain choroid plexus, a structure located within the lateral and fourth ventricles, thereby effectively targeting the blood-cerebrospinal fluid (CSF) barrier. These findings highlight the potential of combining advanced targeting strategies with high-resolution imaging to study sEV interactions with the brain biological barriers and develop more effective CNS therapies.