Precision Delivery of Siponimod through Nanoemulsions: Shaping the Future of Multiple Sclerosis Management

Abstract

Multiple Sclerosis (MS) is a chronic immune-mediated neurodegenerative disorder characterized by demyelination of myelin, neuroinflammatory neurons, and progressive neuronal loss. Although several disease-modifying treatments are available, some of these drugs are not easily bioavailable, cannot penetrate the Blood-Brain Barrier (BBB), or have other adverse effects when administered systemically. Siponimod, a selective Sphingosine-1-Phosphate (S1P1, S1P5) receptor modulator, has shown promising results in the management of disability in secondary progressive MS and in controlling neuroinflammatory activity. However, its lipophilic structure, low aqueous solubility, and high metabolic clearance rate in the liver may limit its therapeutic potential, necessitating the development of more effective delivery methods. The review was carried out using a structured literature search and a method of evidence identification and selection recommended by PRISMA. PubMed, Scopus, Web of Science, and Google Scholar databases were searched for relevant studies published between January 2010 and December 2025. Some of the search terms used were siponimod, “Siponimod” “Nanoemulsion”, “Nanoemulsion-Based Drug Delivery”, “Nanocarrier”, “Multiple Sclerosis”, “Secondary Progressive Multiple Sclerosis”, “Neuroinflammation”, “Blood-Brain Barrier”, “CNS Drug Delivery”, and “Brain Targeting”, and brain targeting. Only peer-reviewed research and review articles published in English were included. Records that already existed, conference abstracts, editorials, letters, non-English publications, and studies without scientific relevance or full texts were not duplicated. Qualitative synthesis was conducted following the screening of retrieved records using the title, abstract, and full text. The summary of the reviewed literature indicates that nanoemulsion technology-based drug delivery systems may provide several advantages for the delivery of lipophilic therapeutic agents, such as increased solubility, stability, permeability, and facilitation of BBB transport. Controlled drug release, enhanced bioavailability, and decreased systemic toxicity are additional potential benefits of nanoemulsions via targeted delivery methods. Existing evidence points to the promise of nanotechnology-based formulations to optimize the delivery of drugs to the central nervous system and enhance the therapeutic response in MS. However, studies focusing on the direct examination of siponimod-loaded nanoemulsions are still limited and represent a gap in the research. The present review emphasizes that nanoemulsion-based drug delivery is a promising approach to address the major drawbacks of siponimod therapy in MS. Siponimod is clinically effective in secondary progressive multiple sclerosis; however, its poor aqueous solubility, high rate of hepatic metabolism, and low brain-targeting efficiency may diminish its therapeutic efficacy. Nanoemulsion systems can help increase the solubility of the drug, improve oral bioavailability, help the drug cross the blood-brain barrier, allow for controlled drug release, and allow for higher concentration of drug at the target site with less systemic side effects. Studies on the delivery of lipophilic neurotherapeutics using nanoemulsions provide evidence supporting the feasibility of this approach for CNS disorders. However, direct preclinical and clinical research on siponimod-loaded nanoemulsions is still limited, and there is a research gap. Formulation optimization, efficacy in vivo, pharmacokinetics, safety aspects for long-term use, and clinical translation of the nanoemulsion formulation of siponimod should be investigated in future studies to establish it as a precision therapeutic approach for MS. Nanoemulsion technology is a promising platform for the precision delivery of siponimod in MS management. Nanoemulsion systems, incorporating nanotechnology and neurotherapeutic design, can help maximize the efficacy of the drug, reduce undesirable side effects, and increase its efficiency in the delivery system. The nanoemulsion-based siponimod formulation is an exciting prospect for the future safe, effective, and targeted management of MS; however, further preclinical and clinical research is needed.