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<p>Multiple sclerosis (MS) is a debilitating neurological disorder involving concurrent immune-mediated demyelination and progressive neurodegeneration. Although disease-modifying therapies (DMTs) effectively modulate peripheral immune responses and reduce relapse rates, they are ineffective at halting disease progression and promoting central nervous system (CNS) repair. This review outlines a new therapeutic approach that targets two important microRNAs: miR-219, which stimulates oligodendrogenesis and remyelination, and miR-146a, which regulates innate immune responses and neuroinflammation. We present compelling evidence showing that the dysregulation of these microRNAs establishes a cycle of inflammatory damage and regenerative failure in chronic MS lesions. Preclinical models show that supplementing with miR-219 drives oligodendrocyte precursor cell (OPC) differentiation and myelin restoration by repressing critical inhibitors, such as PDGFRα and LINGO-1. Concurrently, miR-146a modulates neuroinflammatory cascades by regulating the NF-κB pathway, promoting the polarization of microglia toward a protective M2 phenotype, and enhancing OPC maturation. Despite its therapeutic potential, there are significant challenges to its translation, including optimizing CNS-targeted delivery systems, navigating microRNA pleiotropy, and establishing biomarker-driven treatment paradigms. We propose that a dual-targeting approach leveraging advanced nanocarriers for spatiotemporal microRNA delivery represents a transformative frontier in MS therapeutics, potentially bridging the critical gap between immunomodulation and genuine neurorestoration.</p>

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Dual-Targeting miR-219 and miR-146a in Multiple Sclerosis: Bridging Myelin Repair and Neuroinflammation for Novel Therapeutic Insights

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月7日

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  • Abdullah Yadegari,
  • Fatemeh Tahmasebi,
  • Elmira Roshani Asl,
  • Zeinab Vahidinia,
  • Shirin Barati

摘要

Multiple sclerosis (MS) is a debilitating neurological disorder involving concurrent immune-mediated demyelination and progressive neurodegeneration. Although disease-modifying therapies (DMTs) effectively modulate peripheral immune responses and reduce relapse rates, they are ineffective at halting disease progression and promoting central nervous system (CNS) repair. This review outlines a new therapeutic approach that targets two important microRNAs: miR-219, which stimulates oligodendrogenesis and remyelination, and miR-146a, which regulates innate immune responses and neuroinflammation. We present compelling evidence showing that the dysregulation of these microRNAs establishes a cycle of inflammatory damage and regenerative failure in chronic MS lesions. Preclinical models show that supplementing with miR-219 drives oligodendrocyte precursor cell (OPC) differentiation and myelin restoration by repressing critical inhibitors, such as PDGFRα and LINGO-1. Concurrently, miR-146a modulates neuroinflammatory cascades by regulating the NF-κB pathway, promoting the polarization of microglia toward a protective M2 phenotype, and enhancing OPC maturation. Despite its therapeutic potential, there are significant challenges to its translation, including optimizing CNS-targeted delivery systems, navigating microRNA pleiotropy, and establishing biomarker-driven treatment paradigms. We propose that a dual-targeting approach leveraging advanced nanocarriers for spatiotemporal microRNA delivery represents a transformative frontier in MS therapeutics, potentially bridging the critical gap between immunomodulation and genuine neurorestoration.