Intranasal delivery of dimethyl fumarate and monomethyl fumarate using hyaluronic acid-based hybrid nanoparticles to enhance CNS bioavailability

Dimethyl fumarate (DMF) and its active metabolite monomethyl fumarate (MMF) are first-line oral therapies for
multiple sclerosis (MS), but their clinical use is limited by gastrointestinal side effects and low bioavailability. To
overcome these limitations, this study reports the development and optimization of hyaluronic acid (HA)-
modified lipid–polymer hybrid nanoparticles (LPNs) for intranasal administration, aimed at enhancing central
nervous system (CNS) delivery of DMF via the nose-to-brain route. LPNs were prepared and fully characterized
for physicochemical properties, including particle size (209–230 nm) and zeta potential (ranging from +0.28 to
− 19.6 mV), influenced by HA surface modification. The presence of HA in the LPNs enhanced DMF chemical
stability, mucoadhesiveness, and significantly improved in vitro DMF release and permeation compared to free
DMF suspension. Stability assays revealed rapid hydrolysis of DMF in rat whole blood, while MMF exhibited
greater stability. Pharmacokinetic analysis in rats showed that following intravenous administration of free DMF,
DMF was undetectable in blood and cerebrospinal fluid (CSF), with only MMF present in blood. Similarly,
intranasal administration of free DMF suspension resulted in no detectable levels of DMF or MMF in blood and in
the CSF. In contrast, intranasal delivery of LPNs enabled DMF brain targeting via the nose-to-brain pathway, with
no systemic exposure. These findings demonstrate that HA-modified LPNs are a promising platform for the
intranasal delivery of DMF, potentially reducing side effects and offering new therapeutic perspectives for the use of this drug in MS management.