Therapeutic potential of retinoic acid-loaded lipid Nanocapsules in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis.

Multiple sclerosis (MS) is a chronic neuroinflammatory disease affecting over 2.5 million people worldwide. Despite available therapies, no current treatment halts disease progression or specifically targets remyelination. Here, we evaluated for the first time the early therapeutic potential of retinoic acid-loaded lipid nanocapsules (LNC RA in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. We first compared intravenous and intranasal administration routes. While transferrin-receptor binding peptide (TfRp)-LNC demonstrated enhanced permeability across an in vitro nasal epithelium model compared to free RA, this did not translate in vivo. TfRp functionalization failed to improve brain accumulation and was associated with systemic toxicity. Based on these findings, unmodified LNC RA administered intravenously was selected for therapeutic evaluation in EAE mice. In an early treatment protocol, LNC RA significantly reduced disease severity in EAE mice. Demyelination was attenuated, with a 2.5-fold reduction in fluoromyelin-negative area in spinal cord tissue. No significant modulation of inflammatory markers was observed. These results highlight LNC RA as a promising platform for the treatment of neuroinflammatory diseases. Further studies will optimize CNS targeting and explore combination strategies with immunomodulatory or pro-remyelinating agents.