Immunomodulatory Nanocarriers in Multiple Sclerosis: Dual Targeting ofMicroglia and Mitochondria for Precision Neurotherapy

The chronic neuroinflammatory and neurodegenerative disease known as Multiple Sclerosis (MS) is characterized by mitochondrial dysfunction and ongoing microglial activation. Developments in nanomedicine have enabled the design of immunomodulatory nanocarriers that target mitochondria and microglia simultaneously, thereby addressing two key pathogenic characteristics. By delivering antioxidants and anti-inflammatory drugs straight to microglia and their mitochondria, these systems increase the effectiveness and specificity of treatment. This review summarizes preclinical research on nanocarriers for delivery to the central nervous system, including liposomes, polymeric nanoparticles, dendrimers, amphiphilic polymer nanoparticles, and modified exosomes, for the years 2020-2025. Functionalized liposomes containing microglia-specific peptides or Toll-like receptor 4 ligands can boost microglial uptake by up to five times, which causes cells to adopt anti-inflammatory characteristics. By incorporating antioxidants such as coenzyme Q₁₀ and N-acetylcysteine, and by using polymeric nanoparticles with mitochondrial- targeting groups, such as triphenyl phosphonium, these nanoparticles improve blood-brain barrier penetration and restore mitochondrial function. Dendrimers and exosomes facilitate effective intracellular and mitochondrial transport, reducing oxidative stress and inflammatory signaling, whereas amphiphilic polymer nanoparticles target scavenger receptors to decrease protein aggregation and neuroinflammation. In MS models, dual-targeting nanocarriers that combine mitochondrial repair and microglial modulation exhibit synergistic neuroprotective effects. Even with promising preclinical findings, there are still obstacles to overcome to achieve clinical translation, scale up production, and ensure long-term safety. Early microglial modulator experiments using sophisticated delivery devices show promise. Finally, dual-targeting immunomodulatory nanocarriers present a new precision neurotherapy strategy for multiple sclerosis. Sustained improvement of clinical pathways, safety, and pharmacokinetics may revolutionize therapeutic approaches and enhance patient outcomes.