REVIEW article
Front. Cell Dev. Biol.
Sec. Molecular and Cellular Pathology
Volume 13 - 2025 | doi: 10.3389/fcell.2025.1674333
This article is part of the Research TopicBrain Endothelial Cells: Future Candidates for Translational Medicine to Intercept Brain InflammationView all 4 articles
Skeleton Keys and Trojan Horses: A Review of Therapeutic Delivery to the Brain
Provisionally accepted
- 1Keck Graduate Institute, Claremont, United States
- 2Scripps College, Claremont, United States
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Background: The advances in genetic medicine that have occurred in the last few decades have been tempered by the challenges in delivering those medicines to the desired organs and cell types. Nowhere has this delivery challenge been greater than in the brain, due to the blood brain barrier (BBB), often illustrated as an impenetrable castle wall. As the need for neurological therapies grows an assortment of Trojan horse and skeleton key strategies have been designed to allow passage of therapeutics through the BBB, These range from designer viral vectors, to cell penetrating peptides that can target cell surface receptors, to genetically modifying hematopoietic stem cells, to lipid nanoparticles that pass through the cell membrane. Results: This review will examine the precise method that each delivery vehicle uses to enter and transverse the endothelial layer of the BBB and enter the brain parenchyma. The advantages and challenges of each delivery strategy will be discussed as will the most recent clinical trials using these technologies. Conclusions: There are several extremely promising delivery vehicles that are able to cross the BBB and deliver genetic therapies to neuronal cells. Several of these delivery vehicles have already been approved for use in patients. As these delivery vehicles become further optimized there is the potential to treat a majority of neurological disease and disorders.
Keywords: blood brain barrier, adeno-associated virus, Lipid nanoparticle, receptor mediatedtranscytosis, cell penetrating peptide, focused ultrasound, Hematopoietic Stem Cells
Received: 27 Jul 2025; Accepted: 06 Oct 2025.
Copyright: © 2025 Bailus and Stoub. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Barbara J Bailus, barbara_bailus@kgi.edu
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.