Advancing through the blood-brain barrier: mechanisms, challenges and drug delivery strategies: Review paper

Ronny Vargas; Noelia Martinez-Martinez; Catalina Lizano-Barrantes; Jorge Andrés Pacheco-Molina; Encarna García-Montoya; María Pilar Pérez-Lozano; Josep María Suñe-Negre; Carlos Suñe; Marc Suñe-Pou

doi:10.5599/admet.2988

Authors

Ronny Vargas Department of Industrial Pharmacy, Faculty of Pharmacy, Universidad de Costa Rica, San José, Costa Rica https://orcid.org/0000-0001-7319-6145
Noelia Martinez-Martinez Department of Pharmacy and Pharmaceutical Technology, and Physical Chemistry, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain https://orcid.org/0009-0008-0079-4353
Catalina Lizano-Barrantes Department of Pharmaceutical Care and Clinical Pharmacy, Faculty of Pharmacy, Universidad de Costa Rica, San José, Costa Rica https://orcid.org/0000-0003-1690-631X
Jorge Andrés Pacheco-Molina Department of Industrial Pharmacy, Faculty of Pharmacy, Universidad de Costa Rica, San José, Costa Rica https://orcid.org/0000-0003-4225-1839
Encarna García-Montoya Department of Pharmacy and Pharmaceutical Technology, and Physical Chemistry, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain https://orcid.org/0000-0003-1576-5586
María Pilar Pérez-Lozano Department of Pharmacy and Pharmaceutical Technology, and Physical Chemistry, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain https://orcid.org/0000-0001-6899-066X
Josep María Suñe-Negre Department of Pharmacy and Pharmaceutical Technology, and Physical Chemistry, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain https://orcid.org/0000-0003-1368-2699
Carlos Suñe Department of Molecular Biology, Institute of Parasitology and Biomedicine “López-Neyra” (IPBLN-CSIC), Granada, Spain https://orcid.org/0000-0002-7991-0458
Marc Suñe-Pou Department of Pharmacy and Pharmaceutical Technology, and Physical Chemistry, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain https://orcid.org/0000-0002-0730-3077

DOI:

https://doi.org/10.5599/admet.2988

Keywords:

Brain delivery, central nervous system, targeted therapy, lipid nanoparticles

Abstract

Background and purpose: The delivery of therapeutics to the central nervous system (CNS) remains a major challenge due to the restrictive nature of the blood-brain barrier (BBB), a key evolutionary feature that preserves brain homeostasis. This review seeks to synthesize current knowledge on BBB composition, physiology, and transport mechanisms, and critically analyses drug delivery strategies aimed at overcoming this barrier and enabling effective CNS therapies. Approach: We conducted a comprehensive narrative review integrating evidence on BBB anatomy, transport and permeability mechanisms, drug delivery optimization strategies, with a particular focus on nanotechnology-based systems, and preclinical evaluation models. Key results: We highlight how a deeper understanding of BBB architecture and dynamic regulation can inform rational design of targeted strategies. Drug delivery approaches are summarized and compared, with emphasis on the potential of nanotechnology-based platforms to enhance CNS drug delivery. Translational considerations, including scalability, reproducibility, and regulatory requirements, are critically addressed. Major challenges identified include receptor saturation, competition with endogenous ligands, disease-specific variability in BBB permeability, and the limited predictive value of current preclinical models. Emerging tools, such as organ-on-chip (for evaluation) and microfluidic mixing (for manufacturing nanomaterials), offer promising means to improve physiological relevance and accelerate translation. Conclusion: Progress in BBB research has laid the groundwork for innovative therapies, but significant hurdles remain. Advancing CNS drug delivery will require collaborative work refining transport-targeting mechanisms, developing standardized preclinical models, and integrating fundamental research, applied nanomedicine, and regulatory science to open new opportunities for treating neurological and psychiatric disorders and brain tumours.

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