Anti-miRNA103/107 encapsulated in transferrin-conjugated lipid nanoparticles crosses blood-brain barrier and reduces brain ischemic damage

Pasquale Cepparulo; Ornella Cuomo; Virginia Campani; Antonio Vinciguerra; Maria Josè Sisalli; Valeria Nele; Serenella Anzilotti; Valeria Valsecchi; Antonella Casamassa; Paola Brancaccio; Antonella Scorziello; Giuseppe De Rosa; Lucio Annunziato; Giuseppe Pignataro

doi:10.1016/j.omtn.2024.102131

Anti-miRNA103/107 encapsulated in transferrin-conjugated lipid nanoparticles crosses blood-brain barrier and reduces brain ischemic damage

Mol Ther Nucleic Acids. 2024 Feb 2;35(1):102131. doi: 10.1016/j.omtn.2024.102131. eCollection 2024 Mar 12.

Authors

Affiliations

¹ Division of Pharmacology, Department of Neuroscience, School of Medicine, "Federico II" University of Naples, Via Pansini, 5 - 80131 Naples, Italy.
² Department of Pharmacy, University Federico II of Naples, Via Domenico Montesano, 49 - 80131 Naples, Italy.
³ Department of Biomedical Sciences and Public Health, School of Medicine, University "Politecnica delle Marche", 60126 Ancona, Italy.
⁴ Department of Science and Technology, University of Sannio, 82100 Benevento, Italy.
⁵ SYNLAB SDN, Via Gianturco, 113 - 80143, Napoli, Italy.

Abstract

MicroRNA (miRNA), by post-transcriptionally regulating the expression of genes involved in stroke response, represents important effectors in stroke pathophysiology. Recently, the 103/107 miRNA family emerged as a possible therapeutic target in stroke, as it controls the expression of sodium calcium exchanger 1, a plasma membrane transporter that plays a fundamental role in stroke pathophysiology. Although the neuroprotective properties of this and other miRNAs are promising, several pharmacokinetic drawbacks remain to be faced for the development of a translatable therapy based on small RNAs in CNS diseases. In the present study, to overcome these limitations, the anti-miRNA103/107 was encapsulated in specific preparations of lipid nanoparticles (LNPs), and their effectiveness was evaluated both in an in vitro model of hypoxia represented by primary neuronal cortical cultures exposed to oxygen and glucose deprivation followed by reoxygenation, and in an in vivo model of stroke obtained in rats exposed to transient occlusion of the middle cerebral artery. The results of the present study demonstrated that the encapsulation of anti-miRNA103/107 in transferrin-conjugated PEG-stabilized LNPs allowed the blood-brain barrier crossing and significantly reduced brain ischemic damage. The present achievements pave the way for the exploitation of a systemic intravenous miRNA delivery strategy in stroke therapy.

Keywords: BBB; MT: Delivery Strategies; Na+/Ca2+ exchanger; antagomir; anti-miR103/107; brain ischemia; miRNA103; microRNA; nanocarrier; nanoparticle; stroke.