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Cited by 358Barrier Structure and Function StudiesNanoparticle-Based Drug DeliveryDrug Transport and Resistance Mechanisms

Evolution of blood–brain barrier in brain diseases and related systemic nanoscale brain-targeting drug delivery strategies

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Han, Liang, Jiang, Chen·2021·Acta Pharmaceutica Sinica B
DOI 10.1016/j.apsb.2020.11.023PMC PMC8424230
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Abstract

Blood–brain barrier (BBB) strictly controls matter exchange between blood and brain, and severely limits brain penetration of systemically administered drugs, resulting in ineffective drug therapy of brain diseases. However, during the onset and progression of brain diseases, BBB alterations evolve inevitably. In this review, we focus on nanoscale brain-targeting drug delivery strategies designed based on BBB evolutions and related applications in various brain diseases including Alzheimer's disease, Parkinson's disease, epilepsy, stroke, traumatic brain injury and brain tumor. The advances on optimization of small molecules for BBB crossing and non-systemic administration routes (e.g., intranasal treatment) for BBB bypassing are not included in this review.

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  • Delivery strategies can be divided into three main approaches, taking into account pathological changes to the BBB in AD: receptor-mediated transport, passive accumulation through disrupted tight junctions, and neuroinflammation-mediated transport.

    “Delivery strategies can be divided into three main approaches, taking into account the pathological changes to the BBB in AD [88]. The first is the use of receptor-mediated transport (RMT), for example, via the transferrin receptor or LRP1 (angiopep-2 peptide). The second is passive accumulation through areas with disrupted tight junction integrity (analogous to the EPR effect), where the optimal”

    From Theranostic Nanoplatforms for Alzheimer's Disease: A Critical Analysis of Conceptual Contradictions (2026) · cites this paper as [88]

    The paper describes receptor-mediated delivery for AD in “Evolutionary RMT and CMT based strategy,” and its “Applications > AD” section describes nanocarriers entering through a compromised BBB. It also presents a “Neuroinflammation based strategy,” but does not establish these as the three main approaches specifically for AD; that strategy is discussed across brain diseases. The AD section further cautions that tight-junction loss alone was insufficient to increase influx of small-molecule drugs. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • RAGE is elevated in AD brain vasculature and activated microglia.

    “To enhance brain enrichment, we exploited the elevated expression of RAGE in AD brain vasculature and activated microglia [ 15, 46, 47 ].”

    From Restores Aβ Clearance by Overcoming PCSK9–LRP1 Dysregulation and TRIB3‐Mediated Autophagy Blockade in Alzheimer's Disease (2026) · cites this paper as [46]

    The Applications > AD section states that RAGE expression increases in AD brain microvasculature and describes using that pathway for drug delivery. It discusses delivering treatments to microglia, but does not say that RAGE expression is elevated in activated microglia; that part of the attributed claim is unsupported. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • AD BBB integrity varies by disease stage rather than remaining static.

    “As Han and Jiang [88] review, AD BBB integrity varies by disease stage rather than remaining static.”

    From Theranostic Nanoplatforms for Alzheimer's Disease: A Critical Analysis of Conceptual Contradictions (2026) · cites this paper as [88]

  • Quantitative characterization of tight junction loss depends on disease progression stage, animal model, and individual differences.

    “They emphasize that “quantitative characterization of tight junction loss depends on disease progression stage, animal model, and individual differences”.”

    From Theranostic Nanoplatforms for Alzheimer's Disease: A Critical Analysis of Conceptual Contradictions (2026) · cites this paper as [88]

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Cited by

Sorted by citations

Authors
Han, L., & Jiang, C.
Affiliations
  • Soochow University (CN)
  • Fudan University (CN)
Corresponding author
Han, Liang
ORCID
Venue
Acta Pharmaceutica Sinica B
Publisher
Elsevier BV
Published
2021-08
Volume
11
Issue
8
Pages
2306-2325
ISSN
2211-3835 (ISSN-L)
DOI
10.1016/j.apsb.2020.11.023
PMC
PMC8424230
OpenAlex
W3114264144
Cited by
358
References
18
Citations by year
2026: 57 · 2025: 92 · 2024: 79 · 2023: 66 · 2022: 53 · 2021: 10
FWCI
3.21
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Pharmaceutica Sinica B (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (81703428, 81973254)
  • Natural Science Foundation of Jiangsu Province (BK20191421)
  • Suzhou University of Science and Technology (SYS2019033)
  • National Key Research and Development Program of China (2017YFE0126900)
  • Priority Academic Program Development of Jiangsu Higher Education Institutions
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
blood-brain barrier, brain drug delivery, nanocarriers, brain disorders, Alzheimer's disease, Parkinson's disease, epilepsy, stroke, traumatic brain injury, brain tumors, BBB crossing, intranasal drug delivery

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