Key points are not available for this paper at this time.
Stroke is the second cause of death in Europe and accounts for the first largest cause of long-term disability worldwide. According to the fifth European Society of Cardiology (ESC) report, the numbers of stroke range from 82. 8 to 213. 4 per 100, 000 inhabitants in eastern European and northern African ESC countries, respectively, with almost superimposable numbers between male and females. 1Timmis A. Townsend N. Gale C. P. Torbica A. Lettino M. Petersen S. E. Mossialos E. A. Maggioni A. P. Kazakiewicz D. May H. T. et al. European Society of Cardiology: Cardiovascular Disease Statistics 2019. Eur. Heart J. 2020; 41 (Erratum in: Eur. Heart J. 2020 41, 4507): 12-85https: //doi. org/10. 1093/eurheartj/ehz859Crossref PubMed Scopus (689) Google Scholar The neuron-centric view of stroke research fostered the interventional pipeline with the largest number of failures during translation up to the end of the nineties, 2Ginsberg M. D. Neuroprotection for ischemic stroke: past, present and future. Neuropharmacology. 2008; 55: 363-389https: //doi. org/10. 1016/j. neuropharm. 2007. 12. 007Crossref PubMed Scopus (648) Google Scholar leading to cooled enthusiasm of the research investors in this field. During the last two decades, moving the focus of research from the neuron toward the neurovascular unit renewed the general interest in the field; increased our knowledge on additional, non-neuronal players (i. e. , endothelial cells, astrocytes, oligodendrocytes) in the pathophysiology of stroke-induced brain damage; and, most of all, opened up attention to unprecedented paths of brain repair, disclosing new markers for therapeutic intervention. 3Arai K. Lo E. H. Wiring and plumbing: Oligodendrocyte precursors and angiogenesis in the oligovascular niche. J. Cereb. Blood Flow Metab. 2021; 41: 2132-2133https: //doi. org/10. 1177/0271678X211014979Crossref PubMed Scopus (12) Google Scholar Despite the cyclopean research effort, it is evident that no acute treatments exist for stroke beyond recanalization, and we are still in search of an effective therapy that can be accessed by the vast majority of the stroke population every year (actually, less than 10% of the stroke population undergoes thrombolysis for the narrow time window eligibility constraint). In this scenario, Cepparulo and colleagues4Cepparulo P. Cuomo O. Campani V. Vinciguerra A. Sisalli M. J. Nele V. Anzilotti S. Valsecchi V. Casamassa A. Brancaccio P. et al. Anti-miRNA103/107 encapsulated in trasnferrin-conjugated lipid nanoparticles crosses the blood-brain barrier and reduces brain ischemic damage. Mol. Ther. Nucleic Acids. 2024;: 102131https: //doi. org/10. 1016/j. omtn. 2024. 102131Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar reasoning, moves from the concept, largely established by previous original data, 5Cerullo P. Brancaccio P. Anzilotti S. Vinciguerra A. Cuomo O. Fiorino F. Severino B. Di Vaio P. Di Renzo G. Annunziato L. Pignataro G. Acute and long-term NCX activation reduces brain injury and restores behavioral functions in mice subjected to neonatal brain ischemia. Neuropharmacology. 2018; 135: 180-191https: //doi. org/10. 1016/j. neuropharm. 2018. 03. 017Crossref PubMed Scopus (23) Google Scholar, 6Pignataro G. Cuomo O. Vinciguerra A. Sirabella R. Esposito E. Boscia F. Di Renzo G. Annunziato L. NCX as a key player in the neuroprotection exerted by ischemic preconditioning and postconditioning. Adv. Exp. Med. Biol. 2013; 961: 223-240https: //doi. org/10. 1007/978-1-4614-4756-6₁9Crossref PubMed Scopus (37) Google Scholar confirming that the 103/107 microRNA (miRNA) family controls the expression of sodium calcium exchanger 1 (NCX1; a plasma membrane transporter that plays an important role in stroke pathophysiology) to prove that post-transcriptionally regulating the expression of this gene is an effective therapeutic target in stroke. To this end, they used the anti-miRNA 103/107 engineered to cross the blood-brain barrier. This methodologically demanding piece of work, using in vitro and in vivo settings, generated control experiments to show that the principle is correct and that the observed minimization of neuronal and brain damage, respectively, warrants further investigation. According to control experimental data, their lipid nanoparticles (LNPs) conjugated with transferrin are efficient in miRNA loading capacity that, notably, results very high without altering their characteristic size (approximately 147. 7 nm), while the larger percentage of the ionizable lipid increased the negative zeta potential. Nevertheless, exposure in vitro of rat cortical neurons to different LNP preparations (initial concentration of 0. 7 mg/mL lipids and 0. 4 mg/mL anti-miRNA) under basal conditions and after 1: 1, 000, 1: 100, and 1: 10 v/v dilution showed the absence of toxicity of LNPs (LNP1–4 configuration), with no changes in mitochondrial oxidative capacity. At variance with these results, LNP1, 3, 4 showed neuroprotection of cortical neurons under oxygen glucose deprivation and re-oxygenation, LNP2 resulting ineffective. The treatment with anti-mirRNA-103/107-loaded LNPs, but not with empty LNPs, increased the expression of neuronal anti-miRNA significantly, linking the neuronal protection to this latter effect. Under ischemia (100 min) reperfusion (24 h) conditions, systemic pre- and post-treatment of rats with four boluses of LNP3-4-loaded anti-mirRNA-103/107 minimize brain cortical damage, and this is coincident with enhanced NCX1 gene product expression; LNP1, but not LNP2, enhanced NCX1 gene product expression, while neither LNP1 or LNP2 afforded neuroprotection. LNP1–4 loaded with scrambled miRNAs did not afford neuroprotection in all respects. Measurement of plasma and tissue levels of anti-mirRNA-103/107 indicates a significant level for over 96 h in plasma and brain tissue, speaking to the favorable pharmacokinetics of the LNPs. The compelling evidence in favor for this biotech intervention, tailored on the solid rational basis provided by previous research work on the role of NCX1 in stroke pathophysiology, mandates that this research work should be developed further for successful translation. In fact, among the several open questions left by this study, it is our opinion that experiments should be carried out to prove that pretreatment with anti-mirRNA-103/107-loaded LNPs is indeed not necessary; if this is not the case, then a better delivery system should be devised because for stroke neuroprotection pretreatment, in general and 18 h in particular, is unacceptable. Other questions should be addressed during further development; for instance, it would be interesting to understand whether or not there is a pharmacokinetic basis (e. g. , redistribution in brain) for the lack of neuroprotection for LNPs that indeed reach the brain and modify significantly NCX1 expression (see, for instance, the case of LNP1). At variance with this latter example, LNP2 yields a significant increase of anti-mirRNA-103/107 but fails to afford neuroprotection; these data, together with those of LNP1, may allude to additional mechanisms (for instance, target disappearance over time), which may deserve further investigation. All authors actively contributed to the writing of this commentary. The authors declare no competing interests.
Bagetta et al. (Wed,) studied this question.