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Intranasal Tat-modified PEG-PCL nanomicelles delivering anti-RelA siRNA attenuate ischemia-reperfusion injury.

Overview

Authors: Mitsuyoshi Fukuda1, Takayuki Oguma2, Taiki Nagatomo1, Taiki Yamaguchi3, Yasuhiro Kosuge4, Toyofumi Suzuki1, Takanori Kanazawa1,3
ORCID iDs: Mitsuyoshi Fukuda, Takayuki Oguma, Taiki Nagatomo, Taiki Yamaguchi, Yasuhiro Kosuge, Takanori Kanazawa
  1. Laboratory of Pharmaceutics, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan
  2. Center for Clinical Research, Hamamatsu University Hospital, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka 431-3192, Japan
  3. Department of Clinical Pharmacology, Graduate School of Biomedical Sciences, Tokushima University, 1-78-1, Shoumachi, Tokushima 770-8505, Japan
  4. Laboratory of Pharmacology, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan
Institutions: Nihon University (Japan); Hamamatsu University School of Medicine (Japan); Hamamatsu University Hospital (Japan); Tokushima University (Japan)
Journal: Molecular therapy. Nucleic acids, volume 37, issue 3, article 103028
Dates: received 7 April 2026; accepted 20 July 2026; published online 21 July 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1016/j.omtn.2026.103028 · PMID 42602868 · PMCID PMC13475413 · OpenAlex W7169880875
Open access: gold, a free copy (OpenAlex)
Status: code on request
Categories: mouse (organism), stroke (population), cellular / molecular (subfield)
Methods: Statistics, Smoothing, state filtering, decompositions
Keywords: MT: delivery strategies, nose-to-brain delivery, polymer micelle, siRNA, NF-κB, RelA, transient middle cerebral artery occlusion, neuroprotection, inflammation inhibition
Topic: RNA Interference and Gene Delivery (Molecular Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: Japan Society for the Promotion of Science
Citations: not cited yet (Europe PMC); 72 references in the paper

Abstract

Inflammatory responses centered on microglial activation are deeply involved in the progression of cerebral ischemia-reperfusion injury, and RelA, a subunit of nuclear factor κB (NF-κB), acts as a central mediator of these responses. In this study, we evaluated the efficacy of a nose-to-brain drug delivery system that combines intranasal administration with polymeric nanomicelles modified with the cell-penetrating peptide Tat (polyethylene glycol [PEG]-polycaprolactone [PCL]-Tat) to deliver RelA-targeting small interfering RNA (siRNA), referred to as siRelA. The PEG-PCL-Tat-siRelA complex exhibited efficient intracellular uptake by BV-2 microglial cells and significantly suppressed RelA mRNA expression. No significant cytotoxicity was observed in BV-2 or primary cultured mouse hippocampal neurons. In addition, the complex showed high siRNA stability in the cerebrospinal fluid. Using a radiolabeled model siRNA, intranasal administration of PEG-PCL-Tat to mice subjected to transient middle cerebral artery occlusion (t-MCAO) significantly enhanced siRNA distribution in ischemic brain regions. Intranasal administration of PEG-PCL-Tat-siRelA significantly reduced the infarct volume in ischemic brain regions of the t-MCAO model mice. Furthermore, suppression of RelA mRNA expression in ischemic brain tissue was accompanied by significant reductions in the mRNA expression of NF-κB-downstream inflammatory cytokines. Taken together, these results suggest that intranasal delivery of siRelA using PEG-PCL-Tat represents a promising novel neuroprotective therapeutic strategy mediated by the modulation of inflammatory responses.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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The paper's code and data availability statement is in the Data section.

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Data

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Data and code availability

The data that support the findings of this study are available from the corresponding author upon reasonable request. All relevant data are included within the article and its supplemental information files.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 2, 28 September 2026

  • Authors: added Mitsuyoshi Fukuda (0009-0007-4383-9702); Takayuki Oguma (0009-0007-7046-9620); Taiki Nagatomo (0009-0005-2730-1297); removed Mitsuyoshi Fukuda; Takayuki Oguma; Taiki Nagatomo
  • Funding: added Japan Society for the Promotion of Science

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 7 authors, 9 keywords, 72 references.

Cite

This paper

Fukuda, M., Oguma, T., Nagatomo, T., Yamaguchi, T., Kosuge, Y., Suzuki, T., & Kanazawa, T. (2026). Intranasal Tat-modified PEG-PCL nanomicelles delivering anti-RelA siRNA attenuate ischemia-reperfusion injury. Molecular therapy. Nucleic acids, 37(3), 103028. https://doi.org/10.1016/j.omtn.2026.103028

BibTeX

@article{fukuda2026intranasal,
author = {Fukuda, Mitsuyoshi and Oguma, Takayuki and Nagatomo, Taiki and Yamaguchi, Taiki and Kosuge, Yasuhiro and Suzuki, Toyofumi and Kanazawa, Takanori},
title = {{Intranasal Tat-modified PEG-PCL nanomicelles delivering anti-RelA siRNA attenuate ischemia-reperfusion injury}},
journal = {Molecular therapy. Nucleic acids},
year = {2026},
month = jul,
volume = {37},
number = {3},
pages = {103028},
publisher = {American Society of Gene \& Cell Therapy},
issn = {2162-2531},
doi = {10.1016/j.omtn.2026.103028},
url = {https://doi.org/10.1016/j.omtn.2026.103028},
pmid = {42602868},
pmcid = {PMC13475413}
}

RIS

TY - JOUR
AU - Fukuda, Mitsuyoshi
AU - Oguma, Takayuki
AU - Nagatomo, Taiki
AU - Yamaguchi, Taiki
AU - Kosuge, Yasuhiro
AU - Suzuki, Toyofumi
AU - Kanazawa, Takanori
TI - Intranasal Tat-modified PEG-PCL nanomicelles delivering anti-RelA siRNA attenuate ischemia-reperfusion injury
T2 - Molecular therapy. Nucleic acids
J2 - Mol Ther Nucleic Acids
PY - 2026
DA - 2026/07/21
VL - 37
IS - 3
SP - 103028
SN - 2162-2531
PB - American Society of Gene & Cell Therapy
DO - 10.1016/j.omtn.2026.103028
UR - https://doi.org/10.1016/j.omtn.2026.103028
LA - en
ER -

CSL-JSON

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