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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\n                    <jats:italic>in situ<\/jats:italic>\n                    nasal gel. G-EVs were isolated via serial centrifugation and double filtration and characterized for particle size (103.5\u2009\u00b1\u20091.09\u00a0nm) and zeta potential (-17.3\u2009\u00b1\u20090.32\u00a0mV) confirming nanoscale uniformity. Teriflunomide was loaded into G-EVs with an entrapment efficiency of 63.24\u2009\u00b1\u20090.75%.\n                    <jats:italic>In vitro<\/jats:italic>\n                    release studies revealed a biphasic drug release profile; an initial burst release of 3% in 24\u00a0h followed by sustained release over 21\u00a0days. The cytotoxicity of the G-EVs, loaded G-EVs and the drug was found to be non-toxic at lower concentrations (&lt;\u20090.5\u00a0mg\/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\u2013gel transition at 34.13\u2009\u00b1\u20090.76\u00a0\u00b0C, with high G\u2032 values indicating more elasticity and stiffness, behaving more like a solid. Mucoadhesion testing confirmed strong retention on mucin through texture analysis and\n                    <jats:italic>in vitro<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1208\/s12249-026-03376-9","type":"journal-article","created":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T23:15:15Z","timestamp":1772838915000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design of a Thermoresponsive Nose-to-Brain Neuromaterial for the Release of Naturally Derived Extracellular Vesicles Delivering Teriflunomide for Multiple Sclerosis"],"prefix":"10.1208","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5438-5485","authenticated-orcid":false,"given":"Naznin","family":"Bhom","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3385-155X","authenticated-orcid":false,"given":"Poornima","family":"Ramburrun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5652-5533","authenticated-orcid":false,"given":"Khonzisizwe","family":"Somandi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3889-1529","authenticated-orcid":false,"given":"Yahya E.","family":"Choonara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,6]]},"reference":[{"key":"3376_CR1","doi-asserted-by":"publisher","unstructured":"Hauser SL, Cree BAC. 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