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

Authors

Mitsuyoshi Fukuda, Takayuki Oguma, Taiki Nagatomo, Taiki Yamaguchi, Yasuhiro Kosuge, Toyofumi Suzuki, Takanori Kanazawa

Published in

Molecular therapy. Nucleic acids. Volume 37. Issue 3. Pages 103028. Sep 08, 2026. Epub Jul 21, 2026.

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.

PMID:
42602868
Bibliographic data and abstract were imported from PubMed on 15 Aug 2026.

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