Oligodendrocyte progenitor cell-specific delivery of lipid nanoparticles loaded with Olig2 synthetically modified messenger RNA for ischemic stroke therapy.

Autor: Xu J; Stroke center, Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 510799, China; Department of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China. Electronic address: xujian26@gzhmu.edu.cn., Wang R; Stroke center, Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 510799, China; Clinical Research Institute, the First People's Hospital of Foshan, Foshan 528000, China., Luo W; Clinical Research Institute, the First People's Hospital of Foshan, Foshan 528000, China., Mao X; Clinical Research Institute, the First People's Hospital of Foshan, Foshan 528000, China., Gao H; Department of Geriatrics, Institute of Translational Medicine, the First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen Second People's Hospital, Shenzhen 518035, China., Feng X; Stroke center, Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 510799, China., Chen G; Department of General Medicine, the First People's Hospital of Foshan, Foshan 528000, China., Yang Z; Stroke center, Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 510799, China. Electronic address: xiaoyangzhihua@126.com., Deng W; Department of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China. Electronic address: dengwb5@mail.sysu.edu.cn., Nie Y; Department of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; Clinical Research Institute, the First People's Hospital of Foshan, Foshan 528000, China. Electronic address: nieych3@mail.sysu.edu.cn.
Jazyk: angličtina
Zdroj: Acta biomaterialia [Acta Biomater] 2024 Jan 15; Vol. 174, pp. 297-313. Date of Electronic Publication: 2023 Dec 13.
DOI: 10.1016/j.actbio.2023.12.009
Abstrakt: The transcription factor Olig2 is highly expressed throughout oligodendroglial development and is needed for the differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes and remyelination. Although Olig2 overexpression in OPCs is a possible therapeutic target for enhancing myelin repair in ischemic stroke, achieving Olig2 overexpression in vivo remains a formidable technological challenge. To address this challenge, we employed lipid nanoparticle (LNP)-mediated delivery of Olig2 synthetically modified messenger RNA (mRNA) as a viable method for in vivo Olih2 protein overexpression. Specifically, we developed CD140a-targeted LNPs loaded with Olig2 mRNA (C-Olig2) to achieve targeted Olig2 protein expression within PDGFRα + OPCs, with the goal of promoting remyelination for ischemic stroke therapy. We show that C-Olig2 promotes the differentiation of PDGFRα + OPCs derived from mouse neural stem cells into mature oligodendrocytes in vitro, suggesting that mRNA-mediated Olig2 overexpression is a rational approach to promote oligodendrocyte differentiation and remyelination. Furthermore, when C-Olig2 was administered to a murine model of ischemic stroke, it led to improvements in blood‒brain barrier (BBB) integrity, enhanced remyelination, and rescued learning and cognitive deficits. Our comprehensive analysis, which included bulk RNA sequencing (RNA-seq) and single-nucleus RNA-seq (snRNA-seq), revealed upregulated biological processes related to learning and memory in the brains of mice treated with C-Olig2 compared to those receiving empty LNPs (Mock). Collectively, our findings highlight the therapeutic potential of multifunctional nanomedicine targeting mRNA expression for ischemic stroke and suggest that this approach holds promise for addressing various brain diseases. STATEMENT OF SIGNIFICANCE: While Olig2 overexpression in OPCs represents a promising therapeutic avenue for enhancing remyelination in ischemic stroke, in vivo strategies for achieving Olig2 expression pose considerable technological challenges. The delivery of mRNA via lipid nanoparticles is considered aa viable approach for in vivo protein expression. In this study, we engineered CD140a-targeted LNPs loaded with Olig2 mRNA (C-Olig2) with the aim of achieving specific Olig2 overexpression in mouse OPCs. Our findings demonstrate that C-Olig2 promotes the differentiation of OPCs into oligodendrocytes in vitro, providing evidence that mRNA-mediated Olig2 overexpression is a rational strategy to foster remyelination. Furthermore, the intravenous administration of C-Olig2 into a murine model of ischemic stroke not only improved blood-brain barrier integrity but also enhanced remyelination and mitigated learning and cognitive deficits. These results underscore the promising therapeutic potential of multifunctional nanomedicine targeting mRNA expression in the context of ischemic stroke.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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