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Advances in Biomedical and Tissue Engineering Strategies to Cross the Blood–Brain Barrier for Next-Generation Treatments Against Neurodegenerative Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: 20 July 2025 | Viewed by 5160

Special Issue Editors


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Guest Editor
3D Bioprinting and Bioimaging Lab, Institute of Biochemistry and Cell Biology (IBBC) - National Research Council (CNR), International Campus “A. Buzzati-Traverso”, Monterotondo Scalo, Rome, Italy
Interests: 3D bioprinting; organ and tissue models; organs-on-a-chip; tissue engineering; hepatology; gastroenterology; neuroscience

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Guest Editor
Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy
Interests: neurodegenerative diseases; neuroinflammation; Alzheimer’s disease; therapeutic strategies

Special Issue Information

Dear Colleagues,

The global burden of neurological disorders, including, among others, Parkinson’s disease (PD), Alzheimer’s disease (AD), and other types of dementia, is rapidly growing at a worldwide level, representing an urgent global health challenge. With the aging population, the neurodegenerative disease-associated disability and mortality rates are expected to skyrocket dramatically over the next few decades if novel and effective cures are not available soon. Furthermore, with the aim of efficaciously treating any central nervous system (CNS) disease, from Alzheimer’s to Parkinson’s, one must address the issue of overcoming the blood–brain barrier (BBB), which represents the main obstacle for effective and safe drug delivery to the whole brain or to a specific area of interest. The BBB is indeed a protective yet semipermeable interface of the neurovascular unit that mediates communication between the CNS and peripheral one. As a matter of fact, because of this selective biological barrier, to reach a significant drug concentration at the site of action in the CNS, the administration of high and repeated doses of the therapeutic agent is needed, thereby causing possible harmful and undesired effects. Taking all of this into account, there is still an urgent need for more advanced, safe, and tailored treatment strategies. Thus, the development of a new generation of neuroprotective cures leveraging emerging nanotechnologies, smart pharmacological tools, and cutting-edge tissue engineering approaches for drug delivery across the BBB will represent a tremendous step forward in this appealing biomedical research field, and in turn, it may point the way to accelerating the development and approval of novel drugs. 

This Special Issue aims to collect original research articles and reviews on the state-of-the-art of novel therapeutic approaches for the prevention and treatment of neurodegenerative diseases, with special attention to the most promising biomedical strategies to overcome the blood–brain barrier issue. Advances, progresses, and open challenges in the search for efficacious and safe cures against neurological disorders based on innovative tissue engineering strategies and nanotechnological solutions to circumvent the biological obstacle of the BBB will be the focus of interest in this Special Issue.

Dr. Manuele Gori
Dr. Livia La Barbera
Guest Editors

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Keywords

  • neurodegenerative diseases
  • Alzheimer’s disease
  • CNS
  • blood–brain barrier
  • drug delivery systems
  • nanocarriers
  • nanomedicine
  • tissue engineering
  • theranostics

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Published Papers (4 papers)

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Research

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18 pages, 3892 KiB  
Article
‘Selected’ Exosomes from Sera of Elderly Severe Obstructive Sleep Apnea Patients and Their Impact on Blood–Brain Barrier Function: A Preliminary Report
by Pauline Guillot, Sebastien Celle, Nathalie Barth, Frederic Roche and Nathalie Perek
Int. J. Mol. Sci. 2024, 25(20), 11058; https://doi.org/10.3390/ijms252011058 - 15 Oct 2024
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Abstract
Obstructive sleep apnea syndrome (OSAS) affects a large part of the aging population. It is characterized by chronic intermittent hypoxia and associated with neurocognitive dysfunction. One hypothesis is that the blood–brain barrier (BBB) functions could be altered by exosomes. Exosomes are nanovesicles found [...] Read more.
Obstructive sleep apnea syndrome (OSAS) affects a large part of the aging population. It is characterized by chronic intermittent hypoxia and associated with neurocognitive dysfunction. One hypothesis is that the blood–brain barrier (BBB) functions could be altered by exosomes. Exosomes are nanovesicles found in biological fluids. Through the study of exosomes and their content in tau and amyloid beta (Aβ), the aim of this study was to show how exosomes could be used as biomarkers of OSAS and of their cognitive disorders. Two groups of 15 volunteers from the PROOF cohort were selected: severe apnea (AHI > 30) and control (AHI < 5). After exosome isolation from blood serum, we characterized and quantified them (CD81, CD9, CD63) by western blot and ELISAs and put them 5 h in contact with an in vitro BBB model. The apparent permeability of the BBB was measured using sodium-fluorescein and TEER. Cell ELISAs were performed on tight junctions (ZO-1, claudin-5, occludin). The amount of tau and Aβ proteins found in the exosomes was quantified using ELISAs. Compared to controls, OSAS patients had a greater quantity of exosomes, tau, and Aβ proteins in their blood sera, which induced an increase in BBB permeability in the model and was reflected by a loss of tight junction’ expression. Elderly patients suffering severe OSAS released more exosomes in serum from the brain compartment than controls. Such exosomes increased BBB permeability. The impact of such alterations on the risk of developing cognitive dysfunction and/or neurodegenerative diseases is questioned. Full article
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13 pages, 2756 KiB  
Article
In Vivo Evaluation of Nose-to-Brain Delivery of Liposomal Donepezil, Memantine, and BACE-1 siRNA for Alzheimer’s Disease Therapy
by David Lee, Andrew M. Shen, Milin Shah, Olga B. Garbuzenko and Tamara Minko
Int. J. Mol. Sci. 2024, 25(19), 10357; https://doi.org/10.3390/ijms251910357 - 26 Sep 2024
Viewed by 1433
Abstract
Our study took an innovative approach by evaluating, in vivo, the efficacy of intranasal (IN) administration of liposomal formulations of donepezil, memantine, and beta-site amyloid precursor protein-cleaving enzyme (BACE-1) siRNA, and their combination as a “triple-drug therapy” in treating Alzheimer’s disease (AD). Female [...] Read more.
Our study took an innovative approach by evaluating, in vivo, the efficacy of intranasal (IN) administration of liposomal formulations of donepezil, memantine, and beta-site amyloid precursor protein-cleaving enzyme (BACE-1) siRNA, and their combination as a “triple-drug therapy” in treating Alzheimer’s disease (AD). Female APP/PS1 homozygous, transgenic mice were used as an AD model. The spatial short-term memory of the APP/PS1 mice was evaluated by a Y-maze behavioral test. IN-administered formulations demonstrated better short-term memory recovery than oral administration. Triple-drug therapy induced short-term memory recovery and lowered beta-amyloid (Aβ) 40 and 42 peptide levels and BACE-1 mRNA expression. Additionally, inflammatory cytokine mRNA expression was downregulated. This innovative approach opens new possibilities for Alzheimer’s disease treatment and nose-to-brain delivery. Full article
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15 pages, 8170 KiB  
Article
Assessment of Mannitol-Induced Chronic Blood–Brain Barrier Dysfunction In Vivo Using Magnetic Resonance
by Ana Sampedro-Viana, Sabela Fernández-Rodicio, José Castillo, Pablo Hervella, María Luz Alonso-Alonso and Ramón Iglesias-Rey
Int. J. Mol. Sci. 2024, 25(18), 9792; https://doi.org/10.3390/ijms25189792 - 10 Sep 2024
Viewed by 1231
Abstract
The blood–brain barrier (BBB) is essential for protection and plays a crucial role in chronic neurological disorders like small-vessel disease and Alzheimer’s disease. Its complexity poses significant challenges for effective diagnostics and treatments, highlighting the need for novel animal models and comprehensive BBB [...] Read more.
The blood–brain barrier (BBB) is essential for protection and plays a crucial role in chronic neurological disorders like small-vessel disease and Alzheimer’s disease. Its complexity poses significant challenges for effective diagnostics and treatments, highlighting the need for novel animal models and comprehensive BBB dysfunction studies. This study investigates chronic BBB dysfunction induction using osmotic disruption via mannitol in healthy adult male Sprague Dawley rats over 12 weeks. Group 1 received 1 bolus/week (2.0 g/kg), Group 2 received 3 boluses/week (1.5 g/kg), and Group 3 received 3 boluses/week (2.5 g/kg). BBB dysfunction was assessed using gadolinium (Gd) infusion and MRI to evaluate location, severity, evolution, and persistence. MR spectroscopy (MRS) examined the brain metabolism changes due to intravenous mannitol, with T2-weighted MRI assessing brain lesions. Biomarkers of neuroinflammation were analyzed in the highest mannitol dose group. Our data show chronic BBB dysfunction primarily in the cortex, hippocampus, and striatum, but not in the corpus callosum of rats under periodic mannitol dosing in groups 1 and 2. MRS identified a distinctive metabolite signature, including changes in alanine, choline, and N-acetyl aspartate in the striatum of Group 1. No significant differences were found in the serum levels of all pro- and anti-inflammatory cytokines analyzed in the high-dose Group 3. This study underscores the feasibility and implications of using osmotic disruption to model chronic BBB dysfunction, offering insights for future neuroprotection and therapeutic strategies research. Full article
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Review

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16 pages, 1196 KiB  
Review
Vesicles: New Advances in the Treatment of Neurodegenerative Diseases
by Domenico Nuzzo, Antonella Girgenti, Laura Palumbo, Flores Naselli, Martina Bavetta, Giovanni Marfia and Pasquale Picone
Int. J. Mol. Sci. 2024, 25(23), 12672; https://doi.org/10.3390/ijms252312672 - 26 Nov 2024
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Abstract
Neurodegenerative diseases are characterized by brain lesions that limit normal daily activities and represent a major challenge to healthcare systems worldwide, with a significant economic impact. Nanotechnology is the science of manipulating matter at the nanoscale, where materials exhibit unique properties that are [...] Read more.
Neurodegenerative diseases are characterized by brain lesions that limit normal daily activities and represent a major challenge to healthcare systems worldwide, with a significant economic impact. Nanotechnology is the science of manipulating matter at the nanoscale, where materials exhibit unique properties that are significantly different from their larger counterparts. These properties can be exploited for a wide range of applications, including medicine. Among the emerging therapeutic approaches for the treatment of neurodegenerative diseases, nanotechnologies are gaining prominence as a promising avenue to explore. Here, we review the state of the art of biological and artificial vesicles and their biological properties in the context of neurodegenerative diseases. Indeed, nanometric structures such as extracellular vesicles and artificial vesicles represent a promising tool for the treatment of such disorders due to their size, biocompatibility, and ability to transport drugs, proteins, and genetic material across the blood–brain barrier to target specific cells and brain areas. In the future, a deeper and broader synergy between materials science, bioengineering, biology, medicine, and the discovery of new, increasingly powerful delivery systems will certainly enable a more applied use of nanotechnology in the treatment of brain disorders. Full article
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