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Blood-brain barrier-penetrative lipid nanoparticles enable systemic delivery of TRIM11 mRNA to disaggregate Tau in Alzheimer's disease models.

Overview

Authors: Yan Zou1, Yujing Sang1, Meng Zheng1, Bingyang Shi1,2
  1. Henan Key Laboratory of Brain Targeted Bio-nanomedicine, Henan International Joint Laboratory of Nanobiomedicine, School of Life Sciences, Henan University, Kaifeng 475004, Henan, China
  2. School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW 2007, Australia
Institutions: Henan University (China); University of Technology Sydney (Australia)
Journal: Cell reports. Medicine, volume 7, issue 3, article 102685
Dates: received 23 September 2025; accepted 13 February 2026; published online 17 March 2026; in print March 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1016/j.xcrm.2026.102685 · PMID 41850230 · PMCID PMC13006394 · OpenAlex W7137852758
Open access: gold, a free copy (OpenAlex)
Status: code on request
Categories: human (organism), mouse (organism), Alzheimer's / dementia (population), cellular / molecular (subfield)
Methods: Statistics, Evoked potentials
Keywords: TRIM11 mRNA, PMPC lipid nanoparticle, PLNP, BBB-targeted mRNA delivery, Tau aggregates degradation, Alzheimer’s disease therapy
MeSH: Alzheimer Disease*, Blood-Brain Barrier*, Lipids*, Nanoparticles*, RNA, Messenger*, tau Proteins*, Tripartite Motif Proteins*, Ubiquitin-Protein Ligases*, Animals, Disease Models, Animal, Hippocampus, Humans, Liposomes, Mice, Mice, Transgenic (* major topic)
Topic: RNA Interference and Gene Delivery (Molecular Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: Natural Science Foundation of Henan Province (242300421089, 232301420064); Henan University; National Natural Science Foundation of China (32271463); Double First Class University Plan
Citations: not cited yet (Europe PMC); 46 references in the paper
Research resources: DYKDDDDK Tag Flag RRID:AB_10950495, GFAP Polyclonal antibody RRID:AB_2109646, TRIM11 RRID:AB_2209210, Iba-1 Polyclonal antibody RRID:AB_2224377, RRID:AB_223647, β3-Tubulin Monoclonal Antibody RRID:AB_2938592, Phospho-Tau (P-Ser396) RRID:AB_3070047, Tau RRID:AB_3070118, GAPDH Monoclonal Antibody RRID:AB_3072260, NF-L Monoclonal Antibody RRID:AB_3072654

Abstract

Hyperphosphorylated Tau aggregates are a central pathological hallmark of Alzheimer’s disease (AD), yet no approved therapy directly targets this process. mRNA therapeutics provide a transient and non-viral option but are limited by the blood-brain barrier (BBB). TRIM11 is an ATP-independent disaggregase that dissolves pathological Tau fibrils and promotes proteasomal clearance. Here, a ligand-free lipid nanoparticle (PLNP) is developed with zwitterionic, acetylcholine-mimetic poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) as a core component and leverages interactions with nAChRs and chTs to enable BBB transcytosis. Systemic PLNP delivery of TRIM11 mRNA yields an 8.1-fold increase in hippocampal accumulation and >30-fold higher neuronal transfection than unformulated mRNA. In 3×Tg-AD mice, PLNP-mTRIM11 reduces P-Ser396- and AT8-positive Tau aggregates, attenuates neuroinflammation, restores synaptic/neuronal integrity, and improves cognition and nest building for ≥3 months. Early prophylactic dosing prevents Tau pathology and preserves cognitive function, supporting PLNP-mTRIM11 for tauopathy therapy.

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

Code

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Data

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Study data are available within the article and its supplementary materials. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

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Versions

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Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 4 authors, 6 keywords, 15 MeSH terms, 4 funders, 46 references, 10 RRIDs.

Cite

This paper

Zou, Y., Sang, Y., Zheng, M., & Shi, B. (2026). Blood-brain barrier-penetrative lipid nanoparticles enable systemic delivery of TRIM11 mRNA to disaggregate Tau in Alzheimer's disease models. Cell reports. Medicine, 7(3), 102685. https://doi.org/10.1016/j.xcrm.2026.102685

BibTeX

@article{zou2026blood,
author = {Zou, Yan and Sang, Yujing and Zheng, Meng and Shi, Bingyang},
title = {{Blood-brain barrier-penetrative lipid nanoparticles enable systemic delivery of TRIM11 mRNA to disaggregate Tau in Alzheimer's disease models}},
journal = {Cell reports. Medicine},
year = {2026},
month = mar,
volume = {7},
number = {3},
pages = {102685},
publisher = {Elsevier},
issn = {2666-3791},
doi = {10.1016/j.xcrm.2026.102685},
url = {https://doi.org/10.1016/j.xcrm.2026.102685},
pmid = {41850230},
pmcid = {PMC13006394}
}

RIS

TY - JOUR
AU - Zou, Yan
AU - Sang, Yujing
AU - Zheng, Meng
AU - Shi, Bingyang
TI - Blood-brain barrier-penetrative lipid nanoparticles enable systemic delivery of TRIM11 mRNA to disaggregate Tau in Alzheimer's disease models
T2 - Cell reports. Medicine
J2 - Cell Rep Med
PY - 2026
DA - 2026/03/01
VL - 7
IS - 3
SP - 102685
SN - 2666-3791
PB - Elsevier
DO - 10.1016/j.xcrm.2026.102685
UR - https://doi.org/10.1016/j.xcrm.2026.102685
LA - en
ER -

CSL-JSON

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