Design of a Thermoresponsive Nose-to-Brain Neuromaterial for the Release of Naturally Derived Extracellular Vesicles Delivering Teriflunomide for Multiple Sclerosis.

Multiple sclerosis is a neuroinflammatory disease characterized by demyelination and progressive neurological decline. Teriflunomide, a first-line immunomodulatory agent, faces limitations due to oral route of administration and systemic toxicity. To overcome these challenges, we developed a nose-to-brain delivery system comprising teriflunomide-loaded ginger-derived extracellular vesicles (G-EVs) embedded in an in situ nasal gel. G-EVs were isolated via serial centrifugation and double filtration and characterized for particle size (103.5 ± 1.09 nm) and zeta potential (-17.3 ± 0.32 mV) confirming nanoscale uniformity. Teriflunomide was loaded into G-EVs with an entrapment efficiency of 63.24 ± 0.75%. In vitro release studies revealed a biphasic drug release profile; an initial burst release of 3% in 24 h followed by sustained release over 21 days. The cytotoxicity of the G-EVs, loaded G-EVs and the drug was found to be non-toxic at lower concentrations (< 0.5 mg/ml). It was observed that drug loading enhanced cellular internalization of the G-EVs. Pluronic F127 and chitosan was used to formulate a thermoresponsive and mucoadhesive nasal gel. Rheological analysis demonstrated a sol-gel transition at 34.13 ± 0.76 °C, with high G' values indicating more elasticity and stiffness, behaving more like a solid. Mucoadhesion testing confirmed strong retention on mucin through texture analysis and in vitro studies. The loaded G-EVs were added to the nasal gel and SEM was performed to confirm uniformity. This formulation could offer a synergistic platform for brain drug delivery, combining the biocompatibility of naturally-derived EVs with the thermoresponsive nasal gel.