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. 2026 Feb:325:123589.
doi: 10.1016/j.biomaterials.2025.123589. Epub 2025 Jul 29.

Lipid nanoparticle-mediated delivery of microRNA-124 reduces neuroinflammation

Zhanjun Ma  1 , Hong Anh Dang  2 , Jingjing Yang  3 , Giulia Rodella  3 , Ariane Mwema  3 , Emily De Lombaerde  4 , Yong Chen  4 , Bruno G De Geest  4 , Vincent van Pesch  2 , Giulio G Muccioli  5 , Anne des Rieux  6
Affiliations

Lipid nanoparticle-mediated delivery of microRNA-124 reduces neuroinflammation

Zhanjun Ma et al. Biomaterials. 2026 Feb.

Abstract

MicroRNAs (miRNAs) regulate many physiological and pathological processes implicated in numerous diseases, including neuroinflammatory disorders. Chronic neuroinflammation is a key feature of neurodegenerative diseases, yet effective medications remain unavailable. Delivery of exogenous miRNAs, such as miRNA-124 (miR-124), shows promise as a therapeutic approach as it promotes microglial polarization towards an anti-inflammatory phenotype. However, the options for robust drug delivery systems to enhance miRNA mimic stability and ability to penetrate the central nervous system (CNS) are limited. Here, for the first time, we propose an LNP formulation optimized for miR-124 delivery to the CNS. We compared several ionizable lipids and selected the one that provided the highest efficiency (both regarding cell uptake, transfection efficiency and inflammation modulation) and the lowest microglia activation (S-Ac7-DOG). In cultured BV2 and primary mixed glial cells, miR-124-LNP treatment downregulated the expression of pro-inflammatory and upregulated anti-inflammatory genes. Furthermore, local delivery into the prefrontal cortex as well as intravenous injection of miR-124-LNP in lipopolysaccharides (LPS)-treated mice effectively reduced inflammation, as evidenced by the lower expression of pro-inflammatory and higher levels of anti-inflammatory cytokines. Thus, we provide a rational screening of clinically relevant LNP ionizable lipids for miRNA delivery, the demonstration of the therapeutic efficacy of miR-124-S-Ac7-DOG LNP in an LPS-induced neuroinflammation model, and finally, a non-viral, clinically translatable delivery system for miRNA therapy in the CNS. Overall, this study highlights LNP as an effective miRNA delivery vehicle for CNS applications and as a versatile platform for exploring gene therapies targeting neuroinflammation.

Keywords: Ionizable biscarbamate lipid; Ionizable lipids; Lipid nanoparticles; Microfluidics; Microglia; RNA delivery; microRNA.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Bruno De Geest and Yong Chen have patent #WO2022136641A1 licensed to etherna. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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